CN115137731B - Application of FLT3 inhibitor and pharmaceutically acceptable salt thereof in preparation of medicines for treating cutaneous T cell lymphoma - Google Patents
Application of FLT3 inhibitor and pharmaceutically acceptable salt thereof in preparation of medicines for treating cutaneous T cell lymphoma Download PDFInfo
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- 201000007241 cutaneous T cell lymphoma Diseases 0.000 title claims abstract description 36
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Classifications
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- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention discloses an application of an FLT3 inhibitor and pharmaceutically acceptable salts thereof in preparing medicines for treating cutaneous T cell lymphoma, wherein the FLT3 inhibitor is Giltetinib (Gilteeritinib) and quezatinib (Quizartiinib), and plays a role in killing CTCL by inhibiting expression of oncogene MYC. Gilterrinib and Quizartiinib can provide treatment means for CTCL patients, especially patients who cannot tolerate Vorinostat side effects, so that the kit has good clinical popularization value.
Description
Technical Field
The invention relates to the field of biotechnology and medicine, in particular to application of an FLT3 inhibitor in preparation of a medicine for treating cutaneous T cell lymphoma.
Background
Cutaneous T Cell Lymphoma (CTCL) is a group of non-hodgkin lymphomas caused by clonal proliferation of T lymphocytes homing to the skin, accounting for 75% -80% of all primary cutaneous lymphomas. Among them, mycosis fungoides (mycosis fungoides, MF) and Szary Syndrome (SS) are the two most common subtypes of CTCL. CTCL is early manifested as skin involvement, but the progressive CTCL can involve systemic organs such as lymph nodes, bone marrow, etc., endangering patient lives. Depending on the disease stage, CTCL treatment may be selected as local or systemic treatment. However, many systemic treatments, including radiation, chemotherapy, and phototherapy, do not significantly extend the survival of late CTCL. Although hematopoietic stem cell transplantation can be the final means for curing CTCL, it is difficult to popularize due to the high risk, technical requirements and high cost. Therefore, how to find effective targeted drugs becomes a urgent problem to be solved in CTCL field.
The FLT3 (FMS-like tyrosine kinase 3) gene encodes a class III receptor tyrosine kinase, playing an important role in the normal development of hematopoietic stem cells. Upon ligand binding, FLT3 dimerizes or autophosphorylates, activating downstream STAT5, MAPK, AKT and other signaling pathways, thereby promoting proliferation, differentiation or inhibiting apoptosis of cells. FLT3 is expressed in tumor cells in most patients with Acute Myeloid Leukemia (AML) and 30% are mutated. Mutations of FLT3 mainly include internal tandem repeat mutations (FLT 3-ITD) and point mutations of the tyrosine kinase domain (FLT 3-TKD). Both mutations can activate FLT3 independent of ligand binding, thereby promoting proliferation and differentiation of AML cells. Currently, specific kinase inhibitors of FLT3 are mainly composed of gilsterinib and quezartinib, and are both used in clinical treatment of AML.
Gilteitinib (Gettinib) of formula C 29 H 44 N 8 O 3 Molecular weight 552.71, IC for FLT3 and AXL 50 The values were 0.29nM and 0.73nM. At 11/28 2018, the FDA approved Gefitinib (trade name Xospata; astella) for the treatment of recurrent or refractory AML with FLT3 mutations, and several clinical studies are currently discussing the efficacy of Gilterrinib alone or in combination with other regimens for the treatment of AML.
Quizartiinib (quinizatinib) has molecular formula of C 29 H 32 N 6 O 4 S, molecular weight 560.7, quizartiinib inhibits autophosphorylation of wild type FLT3 and mutant FLT3-ITD, IC 50 4.1nM and 1.1nM, respectively. Quizartinib hydrochloride, which is approved by the national institute of Pharmaceutical and Medical Device (PMDA) for the development of the first three co-pharmaceuticals, is marketed under the trade name of 18, 6 in 2019For the treatment of relapsed/refractory FLT3-ITD positive AML. Currently, this drug has been approved by the U.S. FDA and european EMA as an orphan drug for the treatment of AML.
Mutations in the FLT3 gene have not been reported in CTCL, and the use of FLT3 inhibitors is currently limited to the treatment of AML. Earlier studies in this group found that gilsterinib and quezartinib both significantly inhibited the growth of CTCL cell lines and primary CTCL cells. The mechanism studies found that these two compounds exert killing effect on CTCL mainly by inhibiting expression of oncogene MYC.
Disclosure of Invention
The invention aims to provide an application of FLT3 inhibitor and pharmaceutically acceptable salt thereof in preparing medicines for treating cutaneous T cell lymphoma, and the application can play a role in killing CTCL by inhibiting expression of oncogene MYC.
In order to achieve the above purpose, the invention provides an application of an FLT3 inhibitor and pharmaceutically acceptable salts thereof in preparing medicines for treating cutaneous T cell lymphoma, wherein the FLT3 inhibitor is Gelteeritinib (Gilteeritinib) and quezatinib (Quizartiinib).
Pharmaceutically acceptable salts of the present invention are those formed from physiologically acceptable bases and/or acids well known to those skilled in the pharmaceutical arts. Suitable salts with physiologically acceptable bases, for example sodium, potassium, calcium and magnesium salts, ammonium salts, and salts with suitable organic bases, for example methylamine, dimethylamine, trimethylamine, piperidine, morpholine and triethanolamine. Suitable salts with physiologically acceptable acids are, for example, salts with inorganic acids, such as halogen acids (in particular hydrochloride or hydrobromide), sulphates and phosphates, and salts with organic acids.
The invention discovers that Gilterrinib and Quizartiinib can obviously inhibit the proliferation of CTCL cells, and exert the effect of killing CTCL by inhibiting the expression of oncogene MYC. Cell experiment results show that Gilterrinib and Quizartiinib can remarkably inhibit CTCL cell proliferation by taking CTCL cell lines (Hut 78, HH and MJ) as cell models.
The invention implements comparative experiments of Gilteeritinib and Quizartiinib and the currently-obtained drug Vorinostat (Vorinostat) for clinically treating CTCL, and discovers that Gilteeritinib and Quizartiinib show stronger inhibition effect at the same concentration. Vorinostat (Vorinostat) is a Histone Deacetylase (HDAC) inhibitor under the chemical name Suberoylanilide hydroxamic acid (SAHA), trade nameThe drug can induce cell cycle arrest and apoptosis, is approved by FDA to be marketed in 10/6 2006, and is used for treating exacerbation, persistence and recurrence or CTCL which is not effective after treatment with two systemic drugs. The most common drug-related adverse reactions can be categorized into 4 symptomatic complexes: gastrointestinal symptoms (diarrhea, nausea, loss of appetite, weight loss, vomiting, constipation), systemic symptoms (fatigue, aversion to cold), hematological abnormalities (thrombocytopenia)Anemia), and dysgeusia (dysgeusia, dry mouth). The most common severe drug-related adverse reactions are pulmonary embolism and anemia. The invention is also the most important clinical value, namely Gilterrinib and Quizartiinib can provide treatment means for CTCL patients, especially patients who cannot tolerate Vorinostat side effects, so the invention has good clinical popularization value.
The invention has the advantages that the invention provides a new application of the FLT3 inhibitor in preparing the medicines for treating the cutaneous T cell lymphoma, and Gilterrinib and Quizartiinib can provide a treatment means for CTCL patients, especially patients who cannot tolerate the Vorinostat side effect, so the invention has good clinical popularization value.
Drawings
FIG. 1 shows that the FLT3 inhibitors Gilterrinib and Quizartiinib inhibit CTCL cell proliferation and induce apoptosis. Gilsterinib treated Hut78 cells were active (a) and cell counts (B) and IC50 (C). The viability of Hut78 cells (D) and cell count (E) were treated. F. Viability assay of Hut78 cells treated with the same concentrations (200 nM) of Gilteritinib, quizartinib and Vorinostat. The results show that gilsterinib and quezartinib have a greater inhibitory effect on Hut78 than Vorinostat.
FIG. 2. Mechanism of inhibition of Hut78 cell proliferation by the FLT3 inhibitor Gilterlinib was examined using quantitative proteomics and kinase proteomics. Quantitative proteomic assays were performed 48h after Hut78 cells were treated with Gilterrinib (1. Mu.M) and the heatmap showed all up-and down-regulated proteins. B. Up-and down-regulated proteins were quantified for proteomic assays, and Gene Oncology (GO) analysis was performed to find that pathways associated with cell cycle and division were significantly modulated. Quantitative kinase proteomic assays were performed 48h after Hut78 cells were treated with gilsterinib (1 μm), and kinase tree analysis found that kinases of the cell cycle related kinase (CDK) family were significantly inhibited. (D) The bar graph enumerates the protein kinases that were most clearly modulated as found by quantitative kinase proteomic detection.
FIG. 3 molecular mechanisms of the FLT3 inhibitors Gilterrinib and Quizartiinib to induce apoptosis of CTCL cells. A. Detection of Gilterrinib by Western blot after treatment of HH cells FLT3 and phosphorylation of downstream Signal molecules STAT5 and AKT were detected. B. Western blot detection of activity/expression of molecules closely related to cell proliferation or cycle after Hut78 and MJ cells were treated with Giltertinib and Quizartinib. The results showed a significant decrease in MYC protein levels. C. Quantitative RT-PCR detection of mRNA levels of MYC genes following Giltertinib and Quizartiinib treatment of Hut78 cells. The results show that MYC gene transcription is significantly inhibited by both compounds.
Detailed Description
The invention will be further illustrated with reference to specific examples. The experimental methods used in the following examples are conventional methods unless otherwise specified. Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention.
Example 1 inhibition of CTCL cell proliferation by the FLT3 inhibitors Giltertinib and Quizartiinib, induction of apoptosis
To study the effect of FLT3 inhibitors gilsterinib and quezartiinib on CTCL cells, CTCL cell lines were treated with 1 μm gilsterinib and quezartiinib and cell viability and cell count were measured using trypan blue staining. The results are shown in FIGS. 1A and B. The method comprises the following specific steps:
1) Hut78 cells were seeded in 24-well plates and treated with 1 μmgiltinib and quezartiinib for 24-48 hours, respectively;
2) Cells from each well were collected, washed twice with normal saline and counted by trypan blue staining (FIGS. 1A, B, D, E);
3) Hut78 cells were treated with gilsterinib at various concentrations (0.01-10000 μm), counted with cck8 after 48h, and the IC50 value of this compound for inhibiting Hut78 cells was calculated to be 228.5nM (fig. 1C);
4) Viability assay of Hut78 cells treated with the same concentrations (200 nM) of Gilteritinib, quizartinib and Vorinostat. The results showed that gilsterinib and quezartinib inhibited Hut78 more strongly than Vorinostat (fig. 1F).
Example 2 inhibition of MYC at the transcriptional level by the FLT3 inhibitors Giltertinib and Quizartiinib
To find the mechanism by which the FLT3 inhibitor giltidinib inhibits CTCL cell growth, we treated Hut78 cells with giltidinib, quantitatively detected changes in intracellular proteins by a number of histological means, including quantitative proteomics (fig. 2A) and phosphoproteomics (fig. 2C), and analyzed the enrichment of the modulated proteins. The results showed that the cell cycle pathway was significantly enriched in all the modulator proteins (fig. 2B), suggesting that gilsterinib inhibited the progression of the cell cycle. At the same time, phosphorylated proteomics identified that the cell cycle kinase (CDK) family was significantly down-regulated (fig. 2c, d), further suggesting that gilsterinib inhibits the progression of the cell cycle. The method comprises the following specific steps:
1) Gilteitinib (1 μM) treated Hut78 cells, collected after 48h and washed once with PBS;
2) Cells were lysed with 2 x SDS without DTT, and a portion of the lysed sample was subjected to quantitative mass spectrometry for protein, all mass spectrometry experiments were performed on a Orbitrap Fusion LUMOS mass spectrometer;
3) The sample is enriched with phosphorylated peptide segments simultaneously, and quantitative phosphorylating group chemical identification is carried out;
4) The samples were simultaneously lysed with SDS-containing 2 XSDS lysate and subjected to Western blot analysis to detect downstream and related signal molecules of FLT 3. The results show that STAT5 and AKT phosphorylation levels downstream of FLT were significantly inhibited. In addition, the important transcription factor MYC that regulates the cell cycle is down-regulated.
5) Gilterrinib and Quizartiinib (1. Mu.M) treated HH (FIG. 3A) or Hut78, MJ cells (FIG. 3B), collected after 48h, washed once with PBS, lysed with Trizol, and mRNA levels of MYC genes were detected by real-time quantitative RT-PCR (FIG. 3C). The results show that gilsterinib and quezartinib both significantly down-regulate MYC mRNA, indicating that both actually inhibit MYC gene expression at the transcriptional level.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (1)
- Use of an FLT3 inhibitor as sole active ingredient in the manufacture of a medicament for the treatment of cutaneous T cell lymphoma, characterized in that said FLT3 inhibitor is gefitinib or quezatinib.
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