WO2021152467A1 - Combinaisons comprenant des composés mimétiques de bh3 et des inhibiteurs de stades précoces de l'autophagie destinées à être utilisées dans le traitement de lymphomes b non hodgkiniens et de leucémies lymphoïdes et/ou myéloïdes - Google Patents

Combinaisons comprenant des composés mimétiques de bh3 et des inhibiteurs de stades précoces de l'autophagie destinées à être utilisées dans le traitement de lymphomes b non hodgkiniens et de leucémies lymphoïdes et/ou myéloïdes Download PDF

Info

Publication number
WO2021152467A1
WO2021152467A1 PCT/IB2021/050610 IB2021050610W WO2021152467A1 WO 2021152467 A1 WO2021152467 A1 WO 2021152467A1 IB 2021050610 W IB2021050610 W IB 2021050610W WO 2021152467 A1 WO2021152467 A1 WO 2021152467A1
Authority
WO
WIPO (PCT)
Prior art keywords
treatment
cell
abt
lymphoma
pharmaceutically acceptable
Prior art date
Application number
PCT/IB2021/050610
Other languages
English (en)
Inventor
Vincenzo CIMINALE
Vittoria RAIMONDI
Francesco CICCARESE
Original Assignee
Universita' Degli Studi Di Padova
Istituto Oncologico Veneto Iov-Irccs
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Universita' Degli Studi Di Padova, Istituto Oncologico Veneto Iov-Irccs filed Critical Universita' Degli Studi Di Padova
Publication of WO2021152467A1 publication Critical patent/WO2021152467A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present invention relates to combinations comprising BH3-mimetic compounds and at early stages authophagy inhibitors and/or pharmaceutically acceptable salts or derivatives thereof, pharmaceutical compositions comprising such combinations and use in the treatment of non-Hodgkin's B-cell lymphomas and lymphoid and/ or myeloid leukemias.
  • the present invention relates to pharmacological combinations comprising BH3-mimetic compounds and at least one at early stages authophagy inhibitor and/or pharmaceutically acceptable salts or derivatives thereof, to pharmaceutical compositions comprising such combinations and to the use of the combinations of the invention and of the compositions containing them for the treatment0 of non-Hodgkin's B-cell lymphomas, preferably for the treatment of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukemia (CLL), marginal zone B-cell lymphoma or mantle cell lymphoma (MCL), and even more preferably for the treatment of DLBCL, as well as in the treatment of lymphoid and/ or myeloid leukemias, preferably in the treatment of T-cell acute lymphoblastic leukemia5 (T-ALL) and acute myeloid leukemia (AML).
  • DLBCL diffuse large B-cell lymphoma
  • CLL chronic lymphocytic leukemia
  • the components of the Bcl-2 family of proteins are the main regulators of mitochondrial- dependent apoptosis in eukaryotic cells and this family is composed of both anti- apoptotic (Bcl-XL, Bcl-2, Bcl-W, Bfl-1, MCL-1) and pro-apoptotic proteins (Bak, Bax, Bid, Bim, Bad, Bik, Bmf, Noxa, Puma).
  • the Bcl-2 protein plays several roles, both physiological and pathological; among the most relevant are the inhibition of apoptosis, which, if altered, can promote aberrant cell survival. Therefore, the inhibition of Bcl-2 protein can reactivate cell death in pathological settings, leading to a better therapeutic response in cancer patients.
  • Bcl-2 which plays a central role in the survival of B lymphocytes, is expressed aberrantly in non-Hodgkin's B-cell lymphomas (neoplasms resulting from B-cell transformation) (Leverson, J.D. and Cojocari, D. Hematologic Tumor Cell Resistance to the BCL-2 Inhibitor Venetoclax: A Product of Its Microenvironment? Front. Oncol. (2016) vol. 8:458. doi: 10.3389/ fonc.2018.00458).
  • Non-Hodgkin's B-cell lymphomas are haematological malignancies that primarily involve lymphoid tissues. Depending on the type, NHLs can be characterized by a painless development or by high aggressiveness.
  • the term "non-Hodgkin's B-cell lymphomas” comprises a number of neoplastic diseases derived from B-cell transformation. The 5 most common types, in order of prevalence, are diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukemia (CLL), marginal zone B-cell lymphoma and mantle cell lymphoma (MCL).
  • DLBCL diffuse large B-cell lymphoma
  • CLL chronic lymphocytic leukemia
  • MCL mantle cell lymphoma
  • T-cell acute lymphoblastic leukemia accounts for 15% of paediatric acute lymphoblastic leukemias and 25% of adult leukemias (Chiaretti, S. and Foa, R. T-cell acute lymphoblastic leukemia. Haematologica (2009) 94(2), 160-162, doi:
  • AML Acute myeloid leukemia
  • AML is the most common type of acute leukemia in adults (about 80% of cases). AML may occur in patients with pre-existing haematological disorders as a result of therapy or, in most cases, de novo, with abnormal proliferation of myeloid cells and monoclonal evolution of the disease. Although progress in AML treatment has led to significant improvements in the treatment of younger patients, prognosis in patients aged 65 years and older, representing the majority of new cases, remains inauspicious (De Kouchkovsky, I. and Abdul-Hay, M. Acute myeloid leukemia: a comprehensive review and 2016 update. Blood Cancer J (2016) 6(7):e441. doi: 10.1038/bcj.2016.50).
  • BH3-mimetics are small molecules capable of antagonizing anti-apoptotic proteins by structurally mimicking the BH3 domain of pro-apoptotic proteins.
  • BH3-mimetic molecules is venetoclax (also known as ABT-199, whose formula is given below), which selectively antagonizes the Bcl-2 protein (Souers, A. J. et al. ABT-199, a potent and selective Bcl-2 inhibitor, achieves antitumor activity while sparing platelets. Nat. Med. (2013) vol. 19, 202-208, doi:10.1038/nm.3048), leading to permeabilization of the external mitochondrial membrane and to the release of cytochrome c which activates the cell death programme for apoptosis.
  • venetoclax also known as ABT-199, whose formula is given below
  • ABT-199 has dramatically improved the prognosis of relapsing/ refractory chronic lymphocytic leukemia (RR-CLL, a form of non-Hodgkin's B-cell lymphoma)
  • RR-CLL chronic lymphocytic leukemia
  • the antitumor activity thereof is highly variable in several haematological tumors, resulting, for example, very promising in the treatment of mantle cell lymphoma (MCL) but ineffective in other non-Hodgkin lymphomas, including diffuse large B-cell lymphoma (DLBCL)
  • DLBCL diffuse large B-cell lymphoma
  • T-cell acute lymphoblastic leukemia In the case of T-cell acute lymphoblastic leukemia (T-ALL), ABT-199 has been tested exclusively on cell lines (in vitro and in vivo) and ex vivo on primary cells isolated from patients. Most T-ALL cell lines have been shown to be highly resistant to ABT-199 treatment. In particular, in this pathology ABT-199 is effective only in respect of immature cells, whereas it is ineffective in mature T-ALL (which constitute about 40% of clinical cases) (Peirs, S. et al. ABT-199 mediated inhibition of BCL-2 as a novel therapeutic strategy in T-cell acute lymphoblastic leukemia. Blood (2014) vol. 25, 3738-3747, doi: 10.1182/blood-2014-05-574566).
  • a phase 2 clinical study demonstrated that ABT-199 in monotherapy resulted in complete remission in only 19% of cases of acute myeloid leukemia (AML) previously treated with other therapies (Konopleva, M. et al. Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov (2016) vol. 10, 1106-1117, doi: 10.1158/2159-8290.CD-16-0313), indicating a high resistance of this disease to the treatment with ABT-199.
  • the Bcl-2 protein is not only involved in the control of apoptosis: Bcl-2, in fact, also resides on the surface of the endoplasmic reticulum, where it sequestrates the Beclin-1 protein, responsible for the formation of autophagosomes, thus suppressing authophagy.
  • authophagy plays a key role in maintaining cell homeostasis and contributes to the resistance to anticancer therapies (Pei, G. et al. Autophagy Facilitates Metadherin-Induced Chemotherapy Resistance Through the AMPK/ ATG5 Pathway in Gastric Cancer. Cell Physiol Biochem (2016) vol. 46, 847-859, doi:10.1159/ 000488742).
  • Apoptosis and authophagy appear, therefore, to be highly interconnected mechanisms (Rubinstein, A. D. and Kimchi, A. Life in the balance - a mechanistic view of the crosstalk between autophagy and apoptosis. / Cell Sci (2012) vol. 125, 5259-5268, doi:10.1242/jcs.H5865), therefore it is reasonable to assume that ABT-199, in addition to releasing pro-apoptotic proteins at the mitochondrial level, can also trigger authophagy by breaking the Bcl-2 binding with Beclin-1. In the tumor context, authophagy has been described as a mechanism that favours both death and cell survival (Dalby, K.
  • DLBCL the most common type of non-Hodgkin's B-cell lymphoma, T-ALL and AML are neoplasms characterized by strong intrinsic resistance to ABT-199
  • treatment of patients with these diseases is severely limited in clinical practice compared to neoplasms such as CLL, therefore, the development of a new strategy to overcome cancer cell resistance to antitumor therapy with ABT-199 is extremely important.
  • ABT-199 a need is particularly felt for a reduction in the doses of ABT-199 necessary to achieve a therapeutic effect, in order to reduce the toxic effects of this active substance, which in particular manifest themselves as neutropenia, nausea, anaemia, diarrhoea, upper respiratory tract infection, fatigue, thrombocytopenia, male infertility.
  • the toxicity of ABT-199 is reported also against normal B lymphocytes, which represent the healthy counterpart of DLBCL. This feature of ABT-199 requires a strategy that allows to widen the therapeutic window thereof so as to eliminate tumor cells using low doses of drug.
  • Treatment regimens based on the combination of standard chemotherapy (R-CHOP) and ibrutinib have been proposed for the treatment of DLBCL, which, while showing significant progress, did not enable to decrease the proportion of about 40% of patients with DLBCL that is currently incurable.
  • Treatment of T-ALL involves a combination of corticosteroids (dexamethasone or prednisone), vincristine, L-asparaginase and an anthracycline (daunorubicin or doxorubicin). Although this therapy leads to complete remission in a high proportion of paediatric patients, about 20% of cases do not respond or have relapses and are therefore currently incurable.
  • AML AML Treatment of AML involves two stages, induction of remission and maintenance, with chemotherapy based on cytarabine, daunorubicin and etoposide, or arsenic trioxide and all-trans retinoic acid.
  • Targeted therapies are also available for the treatment of this disease.
  • 50% of elderly patients (over 65 years of age) cannot be treated with intensive chemotherapy due to toxicity, resulting in an inauspicious prognosis (only 25% of patients survive 5 years after diagnosis).
  • An object of the present invention is to overcome the disadvantages of the prior art.
  • non-Hodgkin's B- cell lymphomas preferably for the treatment of diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, marginal zone B-cell lymphoma or mantle cell lymphoma, and even more preferably for the treatment of diffuse large cell B- lymphoma (DLBCL), as well as in the treatment of lymphoid and/ or myeloid leukemias, preferably in the treatment of T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML).
  • T-ALL T-cell acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • BH3- mimetic compounds selected from ABT-199 (venetoclax) or ABT-263 (navithoclax) and at least one at early stages authophagy inhibitor and/ or pharmaceutically acceptable salts or derivatives thereof, selected from Vps34-IN1 and/ or pharmaceutically acceptable salts or derivatives thereof, SAR405 and/ or pharmaceutically acceptable salts or derivatives thereof or Compound 19 and/ or pharmaceutically acceptable salts or derivatives thereof, and by means of pharmaceutical compositions comprising such combinations together with one or more physiologically acceptable excipients.
  • ABT-263 Navitoclax - ABT-263 (navitoclax): IUPAC nomenclature 4-[4-[[2-(4-chlorophenyl)-5,5- dimethylcyclohexene-l-yl]methyl]piperazin-l-yl]-N-[4-[[(2R)-4-morpholin-4-yl-l- phenylsulfanilbutan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl] sulfonylbenzamide.
  • ABT-263 is a BH3-mimetic compound that inhibits anti-apoptotic proteins Bcl-2, Bcl-XL and BCL-W.
  • ABT-263 causes thrombocytopenia in treated patients, since anti-apoptotic protein Bcl- XL plays a key role in platelet survival (Zhang, H. et al.
  • Bcl-2 family proteins are essential for platelet survival.
  • ABT-263 has been chemically modified to reduce the specificity thereof to the anti-apoptotic protein Bcl-2 alone, which is dispensable for platelet survival (Debrincat, M.A. et al. BCL-2 is dispensable for thrombopoiesis and platelet survival. Cell Death Dis (2015) vol. 6, el721, doi: 10.1038/cddis.2015.97), thus giving rise to the BH3-mimetic compound ABT-199.
  • ABT-263 makes it effective even in ABT- 199-resistant tumors that show Bcl-XL overexpression.
  • several clinical trials are underway to assess the safety and the efficacy of this compound as monotherapy or in combination with chemotherapy in haematological and solid tumors.
  • Vps34-IN1 The chemical structure of Vps34-IN1 and the IUPAC nomenclature thereof are reported below:
  • Vps34-IN1 IUPAC nomenclature l-[[5-[2-[(2-chloropyridine-4-yl)amino]pyrimidin-4- yl]-4-(cyclopropylmethyl)pyrimidin-2-yl]amino]-2-methylpropan-2-ol.
  • SAR405 Nomenclature IUPAC (S)-9-((5-chloropyridine-3-yl)methyl)-2-((R)-3- methylmorpholino)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimidine[l,2- a]pyrimidin-4-one.
  • the invention relates to combinations comprising the BH3-mimetic compounds ABT-199 (venetoclax) or ABT-263 (navithoclax) and at least one at early stages authophagy inhibitor and/or pharmaceutically acceptable salts or derivatives thereof, and pharmaceutical compositions comprising such combinations, for use in the treatment of non-Hodgkin's B-cell lymphomas, preferably for the treatment of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukemia, marginal zone B-cell lymphoma or mantle cell lymphoma, and even more preferably for the treatment of diffuse large B-cell lymphoma, as well as in the treatment of lymphoid and/ or myeloid leukemias, preferably in the treatment of T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML), according to the characteristics of the appended claims, which form an integral part of the present description.
  • the at least one at early stages authophagy inhibitor and/ or pharmaceutically acceptable salts or derivatives thereof is preferably Vps34-IN1 and/ or pharmaceutically acceptable salts or derivatives thereof, SAR405 and/or pharmaceutically acceptable salts or derivatives thereof, and/ or Compound 19 and/ or pharmaceutically acceptable salts or derivatives thereof.
  • Another aspect of the present invention proposes a combination comprising ABT-199 (venetoclax) and SAR405 and/or pharmaceutically acceptable salts or derivatives thereof, and pharmaceutical compositions comprising such a combination together with one or more physiologically acceptable excipients.
  • This aspect also relates to the combination comprising ABT-199 (venetoclax) and SAR405 and/ or pharmaceutically acceptable salts or derivatives thereof and the pharmaceutical compositions comprising it, for use in the treatment of non-Hodgkin's B-cell lymphomas, preferably for the treatment of large B-cell diffuse lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukemia, marginal zone B-cell lymphoma or mantle cell lymphoma, and even more preferably for the treatment of diffuse large B-cell lymphoma, as well as in the treatment of lymphoid and/or myeloid leukemias, preferably in the treatment of T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML).
  • T-ALL T-cell acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • Another aspect of the present invention proposes a combination comprising ABT-199 (venetoclax) and Compound 19 and/ or pharmaceutically acceptable salts or derivatives thereof, and pharmaceutical compositions comprising such a combination together with one or more physiologically acceptable excipients.
  • This aspect also relates to the combination comprising ABT-199 (venetoclax) and Compound 19 and/ or pharmaceutically acceptable salts or derivatives thereof and the pharmaceutical compositions comprising it, for use in the treatment of non-Hodgkin's B- cell lymphomas, preferably for the treatment of large B-cell diffuse lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukemia, marginal zone B-cell lymphoma or mantle cell lymphoma, and even more preferably for the treatment of diffuse large B-cell lymphoma, as well as in the treatment of lymphoid and/or myeloid leukemias, preferably in the treatment of T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML).
  • T-ALL T-cell acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • Another aspect of the present invention proposes a combination comprising ABT-263 (navithoclax) and Vps34-IN1 and/ or pharmaceutically acceptable salts or derivatives thereof, and pharmaceutical compositions comprising such a combination together with one or more physiologically acceptable excipients.
  • This aspect also relates to the combination comprising ABT-263 (navithoclax) and Vps34- IN1 and/or pharmaceutically acceptable salts or derivatives thereof and the pharmaceutical compositions comprising it, for use in the treatment of non-Hodgkin's B- cell lymphomas, preferably for the treatment of large B-cell diffuse lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukemia, marginal zone B-cell lymphoma or mantle cell lymphoma, and even more preferably for the treatment of diffuse large B-cell lymphoma, as well as in the treatment of lymphoid and/or myeloid leukemias, preferably in the treatment of T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML).
  • ABT-263 avithoclax
  • Vps34- IN1 pharmaceutically acceptable salts or derivatives thereof
  • pharmaceutical compositions comprising it, for use in the treatment of non-Hodg
  • Another aspect of the present invention proposes a combination comprising ABT-263 (navithoclax) and SAR405 and/or pharmaceutically acceptable salts or derivatives thereof, and pharmaceutical compositions comprising such a combination together with one or more physiologically acceptable excipients.
  • This aspect also relates to the combination comprising ABT-263 (navithoclax) and SAR405 and/or pharmaceutically acceptable salts or derivatives thereof and the pharmaceutical compositions comprising it, for use in the treatment of non-Hodgkin's B- cell lymphomas, preferably for the treatment of large B-cell diffuse lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukemia, marginal zone B-cell lymphoma or mantle cell lymphoma, and even more preferably for the treatment of diffuse large B-cell lymphoma, as well as in the treatment of lymphoid and/or myeloid leukemias, preferably in the treatment of T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML).
  • T-ALL T-cell acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • Another aspect of the present invention proposes a combination comprising ABT-263 (navithoclax) and Compound 19 and/ or pharmaceutically acceptable salts or derivatives thereof, and pharmaceutical compositions comprising such a combination together with one or more physiologically acceptable excipients.
  • This aspect also relates to the combination comprising ABT-263 (navithoclax) and Compound 19 and/ or pharmaceutically acceptable salts or derivatives thereof and the pharmaceutical compositions comprising it, for use in the treatment of non-Hodgkin's B- cell lymphomas, preferably for the treatment of large B-cell diffuse lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukemia, marginal zone B-cell lymphoma or mantle cell lymphoma, and even more preferably for the treatment of diffuse large B-cell lymphoma, as well as in the treatment of lymphoid and/or myeloid leukemias, preferably in the treatment of T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML).
  • T-ALL T-cell acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • physiologically acceptable excipient refers to a substance which lacks any specific pharmacological effect and which does not produce adverse reactions when administered to a mammal, preferably a human being.
  • Physiologically acceptable excipients are well known in the art and are described, for example, in the Handbook of pharmaceutical excipients, sixth-edition (2009), herein incorporated for reference.
  • pharmaceutically acceptable salts or derivatives refers to those salts or derivatives which possess the biological efficacy and properties of the salified or derivatized compound and which do not produce adverse reactions when administered to a mammal, preferably a human being.
  • the pharmaceutically acceptable salts may be inorganic or organic salts; examples of pharmaceutically acceptable salts include, but are not limited to: carbonate, hydrochloride, hydrobromide, sulfate, hydrogen sulfate, citrate, maleate, fumarate, trifluoroacetate, 2-naphthalenesulfonate, and para- toluenesulfonate. Further information on pharmaceutically acceptable salts can be found in the Handbook of pharmaceutical salts, P. Stahl C. Wermuth, WILEY-VCH, 127-133, 2008, incorporated herein for reference.
  • Pharmaceutically acceptable derivatives include esters, ethers and N-oxides.
  • treat refers to a method of alleviating or repealing a disease and/or the associated symptoms thereof, as well as to a method for administering drugs to induce a biological response.
  • composition as used herein is intended to comprise a product comprising the ingredients specified in the specified quantities, as well as any product resulting, directly or indirectly, from the combination of the ingredients specified in the specified quantities.
  • pharmaceutically acceptable it is meant that the vector, diluent or excipient must be compatible with the other components of the formulation and not deleterious to the recipient.
  • authophagy inhibitors refers to pharmacological compounds capable of inhibiting the formation of autophagosomes.
  • PIK3C3/Vps34 is an acronym for "phosphoinositide 3-kinase (PI3K) class III isoform/ vacuolar protein sorting 34", which refers to the phosphatidyllinositol 3-kinase enzyme, class III isoform, involved in the formation of phosphatidyllinositol 3- phosphate, a phospholipid needed for the generation of autophagosomes.
  • PI3K phosphoinositide 3-kinase
  • vacuolar protein sorting 34 refers to the phosphatidyllinositol 3-kinase enzyme, class III isoform, involved in the formation of phosphatidyllinositol 3- phosphate, a phospholipid needed for the generation of autophagosomes.
  • autophagosomes refers to vesicles incorporating intracellular materials (proteins or organelles) intended for degradation by authophagy.
  • mitophagy refers to the degradation through authophagy of damaged or no longer necessary mitochondria.
  • NEL is an acronym for " non-Hodgkin lymphoma” .
  • non-Hodgkin's B-cell lymphomas refers to a series of neoplastic diseases derived from the transformation of B lymphocytes.
  • the 5 most common types of non- Hodgkin's B-cell lymphomas are diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukemia (CLL), marginal zone B-cell lymphoma and mantle cell lymphoma (MCL).
  • DLBCL is an acronym for " diffuse large B-cell lymphoma” .
  • CLL Chronic lymphocytic leukemia
  • RR-CLL is an acronym for refractory/ resistant chronic lymphocytic leukemia.
  • R-CHOP is an acronym where "R” denotes the active substance rituximab; “C” the active substance cyclophosphamide; “H” the active substance hydroxydaunorubicin, also known as doxorubicin; “O” the active substance Oncovin®, also known as vincristine; and “P” the active substance prednisone.
  • T-ALL is an acronym for "T-cell acute lymphoblastic leukemia”.
  • AML is an acronym for "Acute myeloid leukemia”.
  • MCL mantle cell lymphoma
  • PBMC peripheral blood mononuclear cells
  • Bcl-2 is an acronym for "B-cell lymphoma-2 " which refers to a family of genes and their proteins with pro- or anti-apoptotic activity.
  • CC50 Cytotoxic Concentration 50 which indicates the cytotoxic concentration of a compound capable of causing death of 50% of the cells constituting a cell population in vitro.
  • CC30 stands for "Cytotoxic Concentration 30” which indicates the concentration of a compound capable of causing death of 30% of the cells constituting a cell population in vitro.
  • sensitizable cell lines refers to cell lines which have become more susceptible to the cytotoxic action of the BH3-mimetic compounds ABT-199 or ABT-263, thanks to the combined treatment with at least one at early stages authophagy inhibitor, such as for example Vps34-IN1, SAR405 and/ or Compound 19.
  • therapeutic window it is meant the interval between the effective concentration and the toxic concentration of a drug treatment. This parameter defines the safety of the drug treatment itself in relation to the resulting clinical benefit.
  • Figures 1A and IB show the demonstration that DLBCL, AML and T-ALL cell lines are resistant to ABT-199 and ABT-263.
  • the bars represent the CC50 values of ABT-199 in DLBCL, AML and T-ALL cell lines.
  • the dashed line indicates the mean value of CC50 (1.9 Nm) reported in the literature for relapsing/refractory chronic lymphocytic leukemia (RR-CLL).
  • RR-CLL chronic lymphocytic leukemia
  • Figure IB the bars represent the CC50 values of ABT-263 in DLBCL, AML and T-ALL cell lines.
  • the curves indicate the specific cell death, measured by labelling with propidium iodide and cytofluorimetry, in thymocytes, PBMCs and B lymphocytes exposed to increasing concentrations of ABT-199 (1 Nm - 10 mM). Specific cell death was calculated as ((T-NT)/ (100-NT)) ! ⁇ 00, where T indicates the percentage of cells positive for labelling with propidium iodide (PI) and treated with drugs and NT indicates the percentage of cells positive for PI and treated with solvent.
  • Figures 4A, 4B, 4C, 4D, 4E and 4F show the effects of authophagy inhibition on tumor cells and on the corresponding healthy cells.
  • DLBCL, AML and T-ALL cell lines were treated with chloroquine, Vps34-IN1, SAR405 and Compound 19;
  • B lymphocytes, PBMC and thymocytes were treated with chloroquine, Vps34-IN1 and SAR405.
  • the dose- response curves were calculated after 72 hours of treatment for tumor cells and after 48 hours of treatment for healthy cells, analysing specific cell death induced by chloroquine, Vps34-IN1, SAR405 and Compound 19 alone at different concentrations (10-100 mM for chloroquine; 0.25-5 pM for Vps34-IN1, SAR405, Compound 19).
  • FIGs 5 A, 5B and 5C it is indicated how inhibition of authophagy sensitizes cell lines of haematological tumors to ABT-199.
  • the DLBCL, AML and T-ALL cell lines were treated with ABT-199, chloroquine, SAR405 and Compound 19.
  • Dose-response curves were calculated after 72 hours of treatment, analysing ABT-199-induced specific cell death (1 Nm - 10 mM), alone (solid lines) or in combination with authophagy inhibitors (dashed lines). Specific cell death is calculated as described for Figure 2.
  • Figures 6a, 6B and 6C show the effects of combining ABT-199 with authophagy inhibitors in healthy cells.
  • B lymphocytes, PBMC and thymocytes were treated with ABT-199, chloroquine and SAR405.
  • Dose-response curves were calculated after 48 hours of treatment, analysing ABT-199-induced specific cell death (1 Nm - 10 pM), alone (solid lines) or in combination with authophagy inhibitors (dashed lines). Specific cell death is calculated as described for Figure 2.
  • Figures 7 A and 7B show how SAR405 and Compound 19 have a synergistic activity with ABT-199 in the induction of cell death.
  • the isobolographic analysis was carried out in the DLBCL HBL1 cell line treated with ABT-199 (10, 25, 50 and 100 Nm) or SAR405/ Compound 19 at concentrations 1, 2.5, 5 and 10 pM, and with the combination of ABT-199 with SAR405/ Compound 19, maintaining a ratio of BH3-mimetic to authophagy inhibitor equal to 1:100.
  • Combination index values are calculated using CompuSyn software, based on the Chou and Talalay algorithm (Chou, T. C. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res (2010) vol. 70, pages 440-446, doi:10.1158/0008-5472.can-09-1947).
  • FIGs 8A, 8B and 8C it is indicated how inhibition of authophagy sensitizes cell lines of haematological tumors to ABT-263.
  • the DLBCL, AML and T-ALL cell lines were treated with ABT-263, Vps34-IN1, SAR405 and Compound 19.
  • Dose-response curves were calculated after 48 hours of treatment, analysing ABT-263-induced specific cell death (1 Nm - 10 pM), alone (solid lines) or in combination with authophagy inhibitors (dashed lines). Specific cell death is calculated as described for Figure 2.
  • Figure 9 shows how silencing Beclin-1 and Vps34 increases ABT-199-induced cell death.
  • the DLBCL HBL1 cell line was treated with Beclin-1 or Vps34 specific siRNA or with a control siRNA and treated with DMSO, ABT-199 (100 Nm and 1000 Nm) 24 hours after transfection. Specific cell death was measured in cytofluorimetry 48 hours after treatments, as described in Figure 2. The asterisks indicate a statistically significant difference between the indicated samples.
  • Figure 10 shows how electron microscopy analysis suggests the involvement of mitophagia in resistance to ABT-199.
  • the DLBCL OCI Lyl9 line was treated with DMSO, ABT-199 1000 Nm, 50 pM chloroquine and with their combination, fixed in glutaraldehyde 24 hours later and analysed by means of transmission electron microscopy (TEM).
  • TEM transmission electron microscopy
  • the present invention relates to combinations comprising the BH3-mimetic compounds ABT-199 or ABT-263 and at least one at early stages authophagy inhibitor and/or pharmaceutically acceptable salts or derivatives thereof, and to pharmaceutical compositions comprising such combinations; moreover, said combinations and pharmaceutical compositions are the object of the invention for use in the treatment of non-Hodgkin's B-cell lymphomas, preferably for the treatment of diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, marginal zone B-cell lymphoma or mantle cell lymphoma, and even more preferably for the treatment of diffuse large B-cell lymphoma, as well as in the treatment of lymphoid and/ or myeloid leukemias, preferably in the treatment of T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML).
  • T-ALL T-cell acute lymphoblastic leukemia
  • AML acute myeloid leuk
  • authophagy inhibitors and/or pharmaceutically acceptable salts or derivatives thereof are Vps34-IN1 and/ or pharmaceutically acceptable salts or derivatives thereof, SAR405 and/or pharmaceutically acceptable salts or derivatives thereof, and/ or Compound 19 and/ or pharmaceutically acceptable salts or derivatives thereof.
  • the invention relates to a combination comprising ABT-199 and SAR405 and/or pharmaceutically acceptable salts or derivatives thereof, and to the pharmaceutical compositions comprising it; moreover, said combination and the pharmaceutical compositions thereof are the object of the invention for use in the treatment of non-Hodgkin's B-cell lymphomas, preferably for the treatment of diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, marginal zone B-cell lymphoma or mantle cell lymphoma, and even more preferably for the treatment of diffuse large B-cell lymphoma, as well as in the treatment of lymphoid and/or myeloid leukemias, preferably in the treatment of T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML).
  • T-ALL T-cell acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • the invention relates to a combination comprising ABT- 199 and SAR405 and/ or pharmaceutically acceptable salts or derivatives thereof, and to pharmaceutical compositions comprising it; moreover, said combination and the pharmaceutical compositions thereof are object of the invention for use in the treatment of diffuse large B-cell lymphoma, T-cell acute lymphoblastic leukemia and acute myeloid leukemia.
  • the invention relates to a combination comprising ABT-199 and Compound 19 and/or pharmaceutically acceptable salts or derivatives thereof, and to the pharmaceutical compositions comprising it; moreover, said combination and the pharmaceutical compositions thereof are the object of the invention for use in the treatment of non-Hodgkin's B-cell lymphomas, preferably for the treatment of diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, marginal zone B-cell lymphoma or mantle cell lymphoma, and even more preferably for the treatment of diffuse large B-cell lymphoma, as well as in the treatment of lymphoid and/or myeloid leukemias, preferably in the treatment of T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML).
  • T-ALL T-cell acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • the invention relates to a combination comprising ABT-199 and Compound 19 and/or pharmaceutically acceptable salts or derivatives thereof, and to pharmaceutical compositions comprising it; moreover, said combination and the pharmaceutical compositions thereof are the object of the invention for use in the treatment of diffuse large B-cell lymphoma, T-cell acute lymphoblastic leukemia and acute myeloid leukemia.
  • the invention relates to a combination comprising ABT-263 and Vps34-IN1 and/or pharmaceutically acceptable salts or derivatives thereof, and to the pharmaceutical compositions comprising it; moreover, said combination and the pharmaceutical compositions thereof are the object of the invention for use in the treatment of non-Hodgkin's B-cell lymphomas, preferably for the treatment of diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, marginal zone B-cell lymphoma or mantle cell lymphoma, and even more preferably for the treatment of diffuse large B-cell lymphoma, as well as in the treatment of lymphoid and/or myeloid leukemias, preferably in the treatment of T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML).
  • T-ALL T-cell acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • the invention relates to a combination comprising ABT- 263 and Vps34-IN1 and/or pharmaceutically acceptable salts or derivatives thereof, and to pharmaceutical compositions comprising it; moreover, said combination and the pharmaceutical compositions thereof are the object of the invention for use in the treatment of diffuse large B-cell lymphoma, T-cell acute lymphoblastic leukemia and acute myeloid leukemia.
  • the invention relates to a combination comprising ABT-263 and SAR405 and/or pharmaceutically acceptable salts or derivatives thereof, and to the pharmaceutical compositions comprising it; moreover, said combination and the pharmaceutical compositions are the object of the invention for use in the treatment of non-Hodgkin's B-cell lymphomas, preferably for the treatment of diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, marginal zone B-cell lymphoma or mantle cell lymphoma, and even more preferably for the treatment of diffuse large B-cell lymphoma, as well as in the treatment of lymphoid and/ or myeloid leukemias, preferably in the treatment of T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML).
  • T-ALL T-cell acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • the invention relates to a combination comprising ABT-263 and SAR405 and/or pharmaceutically acceptable salts or derivatives thereof, and to pharmaceutical compositions comprising it; moreover, said combination and the pharmaceutical compositions thereof are the object of the invention for use in the treatment of diffuse large B-cell lymphoma, T-cell acute lymphoblastic leukemia and acute myeloid leukemia.
  • the invention relates to a combination comprising ABT-263 and Compound 19 and/or pharmaceutically acceptable salts or derivatives thereof, and to the pharmaceutical compositions comprising it; moreover, said combination and the pharmaceutical compositions thereof are the object of the invention for use in the treatment of non-Hodgkin's B-cell lymphomas, preferably for the treatment of diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, marginal zone B-cell lymphoma or mantle cell lymphoma, and even more preferably for the treatment of diffuse large B-cell lymphoma, as well as in the treatment of lymphoid and/or myeloid leukemias, preferably in the treatment of T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML).
  • T-ALL T-cell acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • the invention relates to a combination comprising ABT-263 and Compound 19 and/or pharmaceutically acceptable salts or derivatives thereof, and to pharmaceutical compositions comprising it; moreover, said combination and the pharmaceutical compositions thereof are the object of the invention for use in the treatment of diffuse large B-cell lymphoma, T-cell acute lymphoblastic leukemia and acute myeloid leukemia.
  • ABT- 199 and ABT-263 against diffuse large B-cell lymphoma (DLBCL), T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML) can be enhanced with specific authophagy inhibitors, such as SAR405 or Compound 19 (in association with ABT-199) and Vps34-IN1, SAR405 or Compound 19 (in association with ABT-263), which, unlike chloroquine, result to be safe for healthy PBMCs, T cells and B cells.
  • This new pharmacological approach can therefore increase the therapeutic window, allowing the selective elimination of resistant cancer cells using lower and less toxic doses of ABT- 199 and ABT-263.
  • compositions for use in the present invention generally comprise an effective amount of the combination object of the invention and a suitable pharmaceutical acceptable vehicle.
  • the compositions can be prepared in a per se known manner, which usually involves mixing the compounds of the combination of the invention with one or more pharmaceutically acceptable carriers and, if desired, in combination with other active pharmaceutical compounds, when necessary under aseptic conditions. Reference is made to standard manuals, such as the latest edition of Remington's pharmaceutical Sciences.
  • the compounds may be formulated as a pharmaceutical preparation comprising at least one compound and at least one pharmaceutically acceptable vehicle, diluent or excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds.
  • the pharmaceutical combinations of the present invention are preferably in a unit dosage form and can be suitably packaged, for example in a box, blister, vial, bottle, sachet, phial or any other suitable single-dose or multidose support or container (which can be properly labelled); optionally with one or more leaflets containing product information and/ or instructions for use.
  • Formulations containing the combination described herein can be prepared using a pharmaceutically acceptable vehicle which is considered safe and effective and can be administered to an individual without causing undesirable biological effects or undesired interactions.
  • the "vector” includes, but is not limited to, diluents, binders, lubricants, disintegrators, fillers, pH modifying agents, preservatives and solubility enhancers.
  • the vector also includes components of the coating composition which may include plasticizers, pigments, colourants, stabilizing agents and glidants. Delayed-release, sustained-release and/or pulsatile-release dosage formulations can be prepared as described in standard references such as "Pharmaceutical dosage forms; Tablets", Ed. Liberman et al. (New York, Marcel Dekker, Inc., 1989), “Remington - the Science and practice of Pharmacy", 20th edition (Lippincott Williams & Wilkins, Baltimore, Maryland, 2000) and “Pharmaceutical dosage forms and drug delivery systems", 6th edition, Ansel et al. (Media, PA: Williams and Wilkins, 1995). These references provide information on supports, materials, equipment and processes for the preparation of tablets and capsules and delayed-release dosage forms of tablets, capsules and granules.
  • ABT-199 or ABT-263 concentrations of ABT-199 or ABT-263 equal to 1, 10, 100, 1000 and 10000 Nm, obtaining the values of CC50 shown in Figures 1 A and IB.
  • concentrations of ABT-199 or ABT-263 were prepared in the dimethylsulfoxide (DMSO) vehicle at an initial concentration 1000 times higher than the final concentration, so that in all cases the solvent was diluted 1:1000 in the culture medium.
  • DMSO dimethylsulfoxide
  • PBMCs Peripheral blood mononuclear cells
  • B lymphocytes and healthy thymocytes were also seeded (lxlO 6 cells/ml culture medium) in 48-well cell culture plates and treated with concentrations of ABT-199 equal to 1, 10, 100, 1000 and 10000 Nm, obtaining the specific cell death values shown in Figure 2.
  • concentrations of ABT-199 were prepared in the dimethylsulfoxide (DMSO) vehicle at an initial concentration 1000 times higher than the final concentration, so that in all cases the solvent was diluted 1:1000 in the culture medium.
  • Specific cell death (%) was measured by labelling with propidium iodide (PI) and cytofluorimetry and was calculated as ((T- NT)/ (100-NT)) !
  • T indicates the percentage of cells treated with drugs positive for PI labelling
  • NT indicates the percentage of cells positive for PI labelling treated with solvent.
  • the B lymphocytes used in these experiments were isolated from mononuclear leukocytes deriving from peripheral blood of healthy donors by immunomagnetic selection using the "B Cell Isolation Kit II, Human” kit (Miltenyi Biotec, Bergisch Gladbach, Germany) according to the manufacturer's instructions.
  • DLBCL OCI Lyl9 cells were seeded (lxlO 6 cells/ ml culture medium) in 6-well cell culture plates and treated with DMSO, ABT-199 1000 Nm, 50 mM chloroquine and the combination of ABT-199 and chloroquine.
  • ABT-199 was prepared in the dimethylsulfoxide (DMSO) vehicle
  • chloroquine was prepared in the H2O vehicle, both at an initial concentration 1000 times higher than the final concentration, so that in all cases the solvent was diluted 1:1000 in the culture medium.
  • the cells were harvested, washed, labelled with the specific fluorophore and analysed by means of the cytofluorimeter as indicated in the protocol provided by the kit manufacturer.
  • MFI mean fluorescence intensity
  • Vps34-IN1 and SAR405 were used, which inhibit the first stages of formation of the autophagosome.
  • DLBCL, AML and T-ALL cell lines were seeded (lxlO 6 cells/ ml culture medium) in 48-well cell culture plates and treated with increasing concentrations of Vps34-IN1 (0.25, 0.5, 1, 2, 5 mM), SAR405 (0.25, 0.5, 1, 2, 5 mM), Compound 19 (0.25, 0.5, 1, 2, 5 pM) or chloroquine (10, 25, 50, 75, 100 pM).
  • Vps34-IN1, SAR405 and Compound 19 were prepared in the solvent dimethylsulfoxide (DMSO), the various concentrations of chloroquine were prepared in the solvent LhO, all at an initial concentration 1000 times higher than the final concentration, so that in all cases the solvent was diluted 1:1000 in the culture medium.
  • Specific cell death (%) was measured by labelling with propidium iodide (PI) and cytofluorimetry and was calculated as ((T- NT)/ (100-NT)) ! ⁇ 00, where T indicates the percentage of cells treated with drugs positive for PI labelling and NT indicates the percentage of cells positive for PI labelling treated with solvent.
  • Vps34-IN1 and SAR405 administered as individual agents do not damage normal B lymphocytes, PBMCs and healthy thymocytes ( Figure 4D, 4E, 4F).
  • the treatment with chloroquine alone leads also to damage to healthy cells ( Figure 4D, 4E, 4F).
  • Normal B cells, PBMCs and healthy thymocytes were seeded (lxlO 6 cells/ ml culture medium) in 48-well cell culture plates and treated with increasing concentrations of Vps34-IN1 (0.25, 0.5, 1, 2, 5 pM), SAR405 (0.25, 0.5, 1, 2, 5 pM) or chloroquine (10, 25, 50, 75, 100 pM).
  • SAR405 does not increase the cytotoxic effect of ABT-199 in B lymphocytes, PBMCs and thymocytes ( Figure 6A, 6B, 6C), suggesting that the inhibition of the early stages of authophagy can drastically improve the clinical efficacy of ABT-199, possibly reducing the side effects thereof and allowing a reduction in dosage.
  • the cells were seeded (lxlO 6 cells/ ml culture medium) in 48-well cell culture plates and treated with concentrations of ABT-199 equal to 10, 25, 50 and 100 Nm, of SAR405 or Compound 19 equal to 1, 2.5, 5 and 10 pM, and with the combination of ABT-199 and SAR405/ Compound 19, maintaining a ratio between the two drug concentrations equal to 1:100.
  • concentrations of ABT-199, SAR405 and Compound 19 were prepared in the solvent dimethylsulfoxide (DMSO), at an initial concentration 1000 times higher than the final concentration, so that in all cases the solvent was diluted 1:1000 in the culture medium.
  • DMSO solvent dimethylsulfoxide
  • EXAMPLE 4 Demonstration of overcoming ABT-263 resistance in DLBCL, AML and T-ALL cell lines using the combinations of ABT-263 with Vps34-IN1, SAR405 or Compound 19.
  • ABT-199 was prepared in the solvent DMSO, chloroquine was prepared in the solvent EhO, both at an initial concentration 1000 times higher than the final concentration, so that in all cases the solvent was diluted 1:1000 in the culture medium. After 24 hours from treatment, the cells were fixed in glutaraldehyde for 30 minutes, washed and kept at 4°C in a 0.1 M cacodylate sodium-based solution at pH 7.4, until inclusion in epoxy resin, cutting into ultrafine sections and subsequent acquisition of images under the microscope. The results show how the mitochondria of cells treated with ABT-199 are dilated and more electron transparent than the mitochondria of vehicle treated cells and how the structure of the ridges is partially compromised. It is interesting to note that in the presence of chloroquine, capable of blocking the degradation of autophagosome, the cells treated with ABT-199 contain debris resembling mitochondria (Figure 10), suggesting that mitophagy may be involved in resistance to ABT-199.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des combinaisons comprenant des composés mimétiques de BH3 et des inhibiteurs de stades précoces de l'autophagie et/ou des sels pharmaceutiquement acceptables ou des dérivés de ceux-ci, des compositions pharmaceutiques comprenant de telles combinaisons et leur utilisation dans le traitement de lymphomes B non hodgkiniens et de leucémies lymphoïdes et/ou myéloïdes. En particulier, la présente invention concerne des combinaisons comprenant les composés mimétiques de BH3 ABT-199 (venetoclax) et au moins l'un des inhibiteurs de stades précoces de l'autophagie choisi parmi SAR405 et le composé 19 et/ou des sels pharmaceutiquement acceptables ou des dérivés de ceux-ci, ou ABT-263 (navithoclax) et au moins l'un des inhibiteurs de stades précoces de l'autophagie choisi parmi V ps34-IN 1, SAR405 et le composé 19 et/ou des sels pharmaceutiquement acceptables ou des dérivés de ceux-ci, des compositions pharmaceutiques comprenant de telles combinaisons, destinées à être utilisées dans le traitement de lymphomes B non hodgkiniens, de préférence dans le traitement du lymphome diffus à grandes cellules B (DLBCL)), du lymphome folliculaire, de la leucémie lymphocytaire chronique, du lymphome à cellules B de la zone marginale ou du lymphome à cellules du manteau, de préférence encore dans le traitement de DLBCL, ainsi que dans le traitement de leucémies lymphoïdes et/ou myéloïdes, de préférence dans le traitement de la leucémie lymphoblastique aiguë des lymphocytes T (T-ALL) et de la leucémie myéloïde aiguë (AML).
PCT/IB2021/050610 2020-01-28 2021-01-27 Combinaisons comprenant des composés mimétiques de bh3 et des inhibiteurs de stades précoces de l'autophagie destinées à être utilisées dans le traitement de lymphomes b non hodgkiniens et de leucémies lymphoïdes et/ou myéloïdes WO2021152467A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT102020000001567 2020-01-28
IT102020000001567A IT202000001567A1 (it) 2020-01-28 2020-01-28 Combinazione comprendente un composto bh3-mimetico e/o suoi sali o derivati farmaceuticamente accettabili e almeno un inibitore di pik3c3/vps34 e/o suoi sali o derivati farmaceuticamente accettabili, composizioni farmaceutiche che comprendano tale combinazione e uso nel trattamento dei linfomi non-hodgkin a cellule b e nel trattamento delle leucemie linfoidi e/o mieloidi.

Publications (1)

Publication Number Publication Date
WO2021152467A1 true WO2021152467A1 (fr) 2021-08-05

Family

ID=71575505

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2021/050610 WO2021152467A1 (fr) 2020-01-28 2021-01-27 Combinaisons comprenant des composés mimétiques de bh3 et des inhibiteurs de stades précoces de l'autophagie destinées à être utilisées dans le traitement de lymphomes b non hodgkiniens et de leucémies lymphoïdes et/ou myéloïdes

Country Status (2)

Country Link
IT (1) IT202000001567A1 (fr)
WO (1) WO2021152467A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114949230A (zh) * 2022-06-13 2022-08-30 厦门大学附属第一医院 一种预防和/或治疗急性髓系白血病的联合用药物组合物及其应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012085815A1 (fr) * 2010-12-21 2012-06-28 Novartis Ag Composés bi-hétéroaryles en tant qu'inhibiteurs de vps34
WO2019070777A2 (fr) * 2017-10-04 2019-04-11 University Of Maryland, Baltimore County Inhibiteurs de kinase pim en combinaison avec des inhibiteurs d'autophagie pour le traitement de cancers

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012085815A1 (fr) * 2010-12-21 2012-06-28 Novartis Ag Composés bi-hétéroaryles en tant qu'inhibiteurs de vps34
WO2019070777A2 (fr) * 2017-10-04 2019-04-11 University Of Maryland, Baltimore County Inhibiteurs de kinase pim en combinaison avec des inhibiteurs d'autophagie pour le traitement de cancers

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
AW ROBERTS ET AL: "Targeting BCL2 With BH3 Mimetics: Basic Science and Clinical Application of Venetoclax in Chronic Lymphocytic Leukemia and Related B Cell Malignancies : Basic science and clinical application of venetoclax", CLINICAL PHARMACOLOGY AND THERAPEUTICS, vol. 101, no. 1, 26 November 2016 (2016-11-26), US, pages 89 - 98, XP055723699, ISSN: 0009-9236, DOI: 10.1002/cpt.553 *
HONDA AYAKO ET AL: "Potent, Selective, and Orally Bioavailable Inhibitors of VPS34 Provide Chemical Tools to Modulate Autophagy in Vivo", ACS MEDICINAL CHEMISTRY LETTERS, vol. 7, no. 1, 14 January 2016 (2016-01-14), US, pages 72 - 76, XP055805814, ISSN: 1948-5875, Retrieved from the Internet <URL:https://pubs.acs.org/doi/pdf/10.1021/acsmedchemlett.5b00335> DOI: 10.1021/acsmedchemlett.5b00335 *
LI MIN ET AL: "Clearance of HIV infection by selective elimination of host cells capable of producing HIV", NATURE COMMUNICATIONS, vol. 11, no. 1, 13 August 2020 (2020-08-13), XP055805852, Retrieved from the Internet <URL:https://www.nature.com/articles/s41467-020-17753-w.pdf> DOI: 10.1038/s41467-020-17753-w *
MARINA KONOPLEVA ET AL: "Efficacy and Biological Correlates of Response in a Phase II Study of Venetoclax Monotherapy in Patients with Acute Myelogenous Leukemia", CANCER DISCOVERY, vol. 6, no. 10, 12 August 2016 (2016-08-12), US, pages 1106 - 1117, XP055642391, ISSN: 2159-8274, DOI: 10.1158/2159-8290.CD-16-0313 *
MOHAMED RAHMANI ET AL: "Inhibition of Bcl-2 antiapoptotic members by obatoclax potently enhances sorafenib-induced apoptosis in human myeloid leukemia cells through a Bim-dependent process", BLOOD, vol. 119, no. 25, 21 June 2012 (2012-06-21), US, pages 6089 - 6098, XP055735345, ISSN: 0006-4971, DOI: 10.1182/blood-2011-09-378141 *
SMITH LINDSAY D ET AL: "BCR signaling contributes to autophagy regulation in chronic lymphocytic leukemia", BLOOD CANCER JOURNAL, NATURE PUBLISHING GROUP UK, LONDON, vol. 34, no. 2, 28 August 2019 (2019-08-28), pages 640 - 644, XP037003027, ISSN: 0887-6924, [retrieved on 20190828], DOI: 10.1038/S41375-019-0557-Y *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114949230A (zh) * 2022-06-13 2022-08-30 厦门大学附属第一医院 一种预防和/或治疗急性髓系白血病的联合用药物组合物及其应用

Also Published As

Publication number Publication date
IT202000001567A1 (it) 2021-07-28

Similar Documents

Publication Publication Date Title
Mohapatra et al. Quinacrine-mediated autophagy and apoptosis in colon cancer cells is through a p53-and p21-dependent mechanism
Zois et al. Radiation-induced autophagy in normal and cancer cells: towards novel cytoprotection and radio-sensitization policies?
US8771754B2 (en) Use of GSK3 inhibitors in combination with radiation therapies
US8318812B2 (en) Therapeutic agents for the treatment of lymphoid malignancies
WO2010033771A2 (fr) Modulateurs de la fonction hsp70/dnak et procedes d&#39;utilisation associes
M Pritchard et al. Progress in small molecule therapeutics for the treatment of retinoblastoma
US20100029683A1 (en) Methods for regulating cell mitosis by inhibiting serine/threonine phosphateses
WO2021116929A1 (fr) Composition comprenant le bh3 mimétique abt-199 (venetoclax) et au moins un inhibiteur de la production de nadph
US20210221805A1 (en) Sigma-2 receptor ligand drug conjugates as antitumor compounds, methods of synthesis and uses thereof
WO2011031842A1 (fr) N-4(-((3-(2-amino-4 pyrimidinyl)-2-pyridinyl)oxy)phényl)-4-(4-méthyl-2- thiényl)-1-phtalazinamine destinée à être utilisée dans le traitement d&#39;un cancer résistant aux agents antimitotiques
EP2946792A1 (fr) Agent thérapeutique et procédé thérapeutique concernant 1,25d3-marrs pour une maladie neurologique telle que la maladie d&#39;alzheimer
WO2019109074A1 (fr) Thérapies anticancéreuses à base de mébendazole et méthodes d&#39;utilisation
KR20160130517A (ko) 혈액학적 장애의 치료에 사용하기 위한 glyt1 억제제
KR20190084291A (ko) 암 치료를 위한 제약 조성물 및 방법
BR112020011167A2 (pt) composição e método para tratar linfoma de célula t periférico e linfoma de célula t cutâneo
WO2021152467A1 (fr) Combinaisons comprenant des composés mimétiques de bh3 et des inhibiteurs de stades précoces de l&#39;autophagie destinées à être utilisées dans le traitement de lymphomes b non hodgkiniens et de leucémies lymphoïdes et/ou myéloïdes
US20160158189A1 (en) Sensitization of cancer cells to apoptosis induction by flavaglines and 5-hydroxy-flavones
EP3782620B1 (fr) Composition pharmaceutique comprenant un dérivé de 1,2-naphtoquinone pour une utilisation dans la prévention ou le traitement de la leucémie aiguë myéloïde ou lymphoblastique
US11524000B2 (en) Targeting Mcl-1 to enhance DNA replication stress sensitivity for cancer therapy
WO2018199109A1 (fr) Agent thérapeutique pour maladies neurodégénératives
US8957106B2 (en) Iminosugar treatment of tumors
KR102154236B1 (ko) 미리세틴을 포함하는 골육종 예방 또는 치료용 약학적 조성물
WO2022087173A1 (fr) Composés de phosphaplatine utilisés en tant qu&#39;agents thérapeutiques ciblant sélectivement des cellules tumorales hautement glycolytiques et leurs procédés
WO2023172669A2 (fr) Polythérapies pour la modulation de la production de lipides
WO2021133862A1 (fr) Ciblage du mécanisme d&#39;apoptose intrinsèque dans le glioblastome

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21708360

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21708360

Country of ref document: EP

Kind code of ref document: A1