WO2021027912A1 - 一种含西达本胺的抗肿瘤药物组合物及其应用 - Google Patents
一种含西达本胺的抗肿瘤药物组合物及其应用 Download PDFInfo
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- WO2021027912A1 WO2021027912A1 PCT/CN2020/109102 CN2020109102W WO2021027912A1 WO 2021027912 A1 WO2021027912 A1 WO 2021027912A1 CN 2020109102 W CN2020109102 W CN 2020109102W WO 2021027912 A1 WO2021027912 A1 WO 2021027912A1
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the invention relates to the field of medicine, in particular to an antitumor pharmaceutical composition containing chidamide and its application.
- Chidamide has a structure of the following formula (1), and its chemical name is N-(2-amino-4-fluorophenyl)-4-[N-[(E)-3-(3-pyridine)acryloyl] Aminomethyl]benzamide.
- Chidamide is a new molecular entity drug discovered exclusively by Shenzhen Chips Biotechnology Co., Ltd., with a novel mechanism. It is the world's first subtype selective histone deacetylase (HDAC) inhibitor and the world's first approved treatment Oral drugs for peripheral T-cell lymphoma belong to the class of epigenetic regulators.
- HDAC histone deacetylase
- Chidamide can re-regulate the epigenetic abnormalities related to the occurrence and development of tumors, and act on the epigenetic related target-histone deacetylase (class I subtypes 1, 2, 3 and IIb Class 10 subtypes).
- Histone deacetylase HDAC is a type of protease that plays an important role in the structural modification of chromosomes and the regulation of gene expression.
- Chidamide acts as an HDAC inhibitor and acts by inhibiting the biological activity of HDAC. Changes in gene expression of multiple signaling pathways for tumorigenesis (ie, epigenetic changes).
- ALK anaplastic lymphoma kinase, anaplastic lymphoma kinase
- ALK anaplastic lymphoma kinase, anaplastic lymphoma kinase
- ALK is a transmembrane receptor tyrosine kinase that can mutate in a variety of malignant tumors or be fused with other oncogenes. It is a tumor-causing driver gene.
- ALK can activate multiple intracellular signaling pathways, including phospholipase C ⁇ , JAK kinase, signal transducer and activator of transcription-3 (STAT3), phosphatidylinositol 3-kinase , PI3K), mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK), etc., are involved in regulating cell growth, transformation and anti-apoptosis.
- ALK gene recombination, mutation or amplification has been found in a variety of tumors, including lymphoma, neuroblastoma and non-small cell lung cancer. In recent years, targeting ALK fusion genes has become a cutting-edge treatment for NSCLC.
- ALK inhibitors include crizotinib, ceritinib, and alectinib.
- c-Met Cellular-mesenchymal epithelial transition factor
- HGFR hepatocyte growth factor receptor
- the c-Met signaling pathway plays a key role in invasive growth during embryonic development and postpartum organ regeneration. Normally, the c-Met signaling pathway in adults is fully activated only in the process of wound healing and tissue regeneration, but the tumor c-Met signaling pathway can be frequently activated by cancer cells, which promotes tumor formation, invasive growth and metastasis.
- the c-Met signaling pathway is abnormally regulated in many types of solid tumors (lung cancer, gastric cancer, liver cancer, breast cancer, skin cancer, colorectal cancer, etc.), and in colorectal cancer liver metastasis, oral squamous It plays an important role in the formation, growth, and metastasis of cancer, the invasion and metastasis of breast, ovarian, and gastric cancer, and the occurrence and development of liver cancer, lung cancer, and pancreatic cancer. Because of the important role of abnormal c-Met signal in human tumor formation, invasion and metastasis. Therefore, inhibiting c-Met signaling has become an important strategy for cancer treatment.
- c-Met inhibitors include erlotinib, gefitinib, cabozatinib, govacatinib, frittinib, tivacinib, crizotinib, and kazatinib.
- ROS1 c-ros proto-oncogene 1, c-ros oncogene 1
- RIKOVA RIKOVA was isolated from lung adenocarcinoma patient tissues for the first time in 2007, with an incidence of approximately 1.0% to 3.4% of NSCLC.
- ROS1 as a new lung cancer driver gene, has been confirmed as a potential new target for NSCLC treatment.
- ROS1 tyrosine kinase controls multiple cell processes such as apoptosis, survival, differentiation and proliferation, and plays an important role in the treatment of various malignant tumors. In recent years, some small molecule inhibitors targeting ROS1 have been reported successively.
- ROS1 inhibitors include crizotinib, ceritinib, brigatinib, AZD-3463, NVP-TAE684, foretinib and cabozantinib, etc., 2-aminopyrimidines, Compounds such as 4-arylaminoquinolines have been reported to have strong ROS1 kinase inhibitory activity. In addition, some selective ROS1 inhibitors have also been developed.
- Crizotinib has the following formula (2) structure, and its chemical name is: 3-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5- [1-(Pyridin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine.
- Crizotinib is an ATP-competitive multi-target protein kinase inhibitor developed by Pfizer to inhibit Met/ALK/ROS. Crizotinib has a significant clinical effect on humans in tumor patients with abnormal ALK, ROS and MET kinase activity. Crizotinib was approved by the US FDA in 2011 as a small molecule targeted drug for the treatment of advanced NSCLC patients with anaplastic lymphoma kinase (ALK) positive. It has been clinically used in the treatment of ALK-positive non-small cell lung cancer.
- ALK aplastic lymphoma kinase
- Crizotinib targets the ALK protein and inhibits the phosphorylation of its tyrosine kinase domain so that it cannot be activated, thereby regulating the activation forms of downstream signaling proteins PI3K, AKT and mTOR, p-PI3K, p-AKT and p- mTOR expression.
- the inventor unexpectedly discovered in the research that the combination of chidamide and c-Met/ALK/ROS1 inhibitor can achieve a synergistic anti-tumor effect.
- the present invention provides an anti-tumor pharmaceutical composition containing chidamide, which contains chidamide and c-Met inhibitor, or contains chidamide and anaplastic lymphoma kinase (anaplastic lymphoma kinase, ALK) inhibitor, or contains Chidamide and repressor of silence 1 (ROS1) inhibitor.
- the c-Met inhibitor includes, but is not limited to, crizotinib, cabozantinib, tivantinib, glumetinib and other drugs with c-Met inhibitory activity.
- the ALK inhibitor includes, but is not limited to, ceritinib, alectinib, crizotinib, brigatinib, repotrectinib, entrectinib, lorlatinib and other drugs with ALK inhibitory activity.
- the ROS1 inhibitor includes, but is not limited to, drugs with ROS1 inhibitory activity such as crizotinib, brigatinib, repotrectinib, entrectinib, and lorlatinib.
- the weight ratio of the chidamide and the c-Met inhibitor is 1:1 to 1:5.
- the weight ratio of the chidamide and the ALK inhibitor is 1:1 to 1:5.
- the weight ratio of the chidamide and the ROS1 inhibitor is 1:1 to 1:5.
- composition of the present invention may also include a pharmaceutically acceptable carrier.
- the present invention also provides the use of the above-mentioned pharmaceutical composition in the preparation of a medicament for the treatment of c-Met, ALK or ROS1 gene amplification, rearrangement, overexpression, or other forms of mutations.
- the malignant tumors include, but are not limited to, lung cancer, stomach cancer, liver cancer, breast cancer, skin cancer, bowel cancer, ovarian cancer, pancreatic cancer, lymphoma, and neuroblastoma.
- the present invention provides a medicine kit containing the above-mentioned pharmaceutical composition.
- the chidamide and c-Met inhibitor, ALK inhibitor or ROS1 inhibitor are unit preparations with the same or different specifications, respectively.
- the chidamide and c-Met inhibitor, ALK inhibitor or ROS1 inhibitor are provided in separate containers.
- the weight ratio of chidamide to c-Met inhibitor, ALK inhibitor or ROS1 inhibitor is 1:1 to 1:5.
- the present invention provides a method for treating malignant tumors, which includes the step of administering a therapeutically effective amount of the above-mentioned pharmaceutical composition or kit to a patient in need.
- the chidamide and c-Met inhibitor, ALK inhibitor or ROS1 inhibitor are administered simultaneously, separately or sequentially.
- the present invention found through MTS experiments that the combined administration of histone deacetylase inhibitor chidamide and c-Met/ALK/ROS1 inhibitor crizotinib can be used in lung cancer cell lines Calu-3, HCC827, NCI- H460, gastric cancer cell line AGS and lymphoma cell line KARPAS-299 have a synergistic inhibitory effect, that is, the combined inhibitory effect of the two drugs on tumor cells is stronger than the sum of the inhibitory effects produced by the two drugs alone.
- the synergistic anti-tumor efficacy of chidamide and crizotinib was verified on the HCC827 and KARPAS-299 nude mouse xenograft models.
- Figure 1 Chidamide synergistically sensitizes c-Met/ALK/ROS1 inhibitor (crizotinib) in lung cancer cell lines;
- Figure 2 Chidamide synergistically sensitizes c-Met/ALK/ROS1 inhibitor (crizotinib) in gastric cancer and lymphoma cell lines;
- Figure 3 Synergistic anti-tumor efficacy of chidamide and c-Met/ALK/ROS1 inhibitor (crizotinib) in combination in nude mouse animal experiments.
- the present invention discloses the combination of chidamide and c-Met/ALK/ROS1 inhibitor and its use in the treatment of cancer.
- Those skilled in the art can learn from the content of this article and appropriately improve the process parameters.
- all similar substitutions and modifications are obvious to those skilled in the art, and they are all deemed to be included in the present invention.
- the applications and pharmaceutical compositions of the present invention have been described through preferred embodiments, and relevant personnel can obviously modify or appropriately modify the applications and pharmaceutical compositions described herein without departing from the content, spirit and scope of the present invention In combination with, to realize and apply the technology of the present invention.
- Human lung cancer cell lines Calu-3, HCC827, NCI-H460, human gastric cancer cell line AGS and human lymphoma cell line KARPAS-299 were all purchased from the American Type Culture Collection (ATCC) at 37°C, Routine culture under the condition of 5% CO2, among which the culture medium of HCC827, NCI-H460 and KARPAS-299 is RPMI-containing 10% Fetal bovine serum (FBS; Gibco) and 1% Penicillin-Streptomycin (HyClone) 1640(Gibco), the culture medium of Calu-3 is minimum Eagle's medium (MEM, Gibco) containing 10% FBS and 1% Penicillin-Streptomycin, and the culture medium of AGS is F12( containing 10% FBS and 1% Penicillin-Streptomycin Gibco). Trypsin was purchased from Gibco; MTS cell activity detection kit was purchased from Promega. Nude mice were purchased from Guangdong Medical Laboratory Animal Center.
- ATCC American Type Culture Collection
- the adherent culture cell lines Calu-3, HCC827, NCI-H460, AGS were digested and collected by Trypsin and counted.
- MTS cell viability detection reagent After 144 hours of drug treatment, add 20 ⁇ L MTS cell viability detection reagent to each well, where the volume ratio of MTS and PMS is 20:1, and add the same volume of culture medium and MTS cell viability detection reagent to the wells without cells as the detection background ( OD490-BLK). After incubating at 37°C for about 1 hour, read the absorbance value of each well at a wavelength of 490nm with a microplate reader. After subtracting OD490-BLK from the reading of each well, the OD490-T of each dosing well and the OD490-T0 of the negative control well were obtained after deducting the detection background.
- the relative survival rate of cells in each dosing hole is calculated according to the following formula:
- Relative cell growth rate OD490-T/OD490-T0 ⁇ 100%
- Figure 1b shows the dose-dependent proliferation inhibitory effects of crizotinib single agent and 0.5 ⁇ M chidamide combined with gradient doses of crizotinib on the above three cell lines, and crizotinib single agent on three lung cancers
- the GI50 of the cell line was 2.546 ⁇ M, 1.052 ⁇ M, and 1.668 ⁇ M, respectively.
- crizotinib was used in combination with 0.5 ⁇ M chidamide
- the GI50 of the three cell lines ( crizotinib ) The combined) were 1.117 ⁇ M, 0.336 ⁇ M, and 1.114 ⁇ M, respectively.
- the apparent GI50 cedaramide combined
- GI50 Chidamide monotherapy
- GI50 g oxadiazol erlotinib monotherapy
- GI50 g oxadiazol United erlotinib
- CI GI50 (Cizoderamide combined) /GI50 (Cizodamine single agent) +GI50 ( Crizotinib combined) /GI50 ( Crizotinib single agent)
- KARPAS-299 cells cultured in suspension a large number of expansions were also carried out and the cells were maintained in a logarithmic growth state. After the number of cells reached the required amount, the cell pellets were collected by centrifugation, washed twice with a large amount of PBS to remove serum components, centrifuged at 800 rpm for 10 minutes at room temperature, and the supernatant was discarded. Resuspend the cells in RPIM-1640 medium without FBS and adjust the cell concentration to 10 7 /300 ⁇ L.
- the tumor-forming nude mice were randomly divided into four groups (ie solvent control group, chidamide group, crizotinib group and combination medication group), labeled and raised in cages, and were administered and observed in groups every day Tumor growth. Measure the body weight of each nude mouse before administration, and calculate the dose per kilogram of body weight.
- the solvent control group is based on 10 ⁇ L of CMC-Na solution per gram of body weight, and 10 mg/kg of chidamine 10 ⁇ L of 1 mg/mL crizotinib-CMC-Na suspension, 25 mg/kg of crizotinib per gram of body weight 2.5 mg/mL crizotinib-CMC-Na suspension
- the combination medication group was administered intragastrically with a CMC-Na suspension containing 2.5 mg crizotinib and 1 mg chidamide per milliliter of 10 ⁇ L per gram of body weight; in KARPAS-299 nude mice, the solvent control group 10 ⁇ L of CMC-Na solution per gram of body weight, 2 mg/kg of Chidamide per gram of body weight 0.2 mg/mL Cedaramide-CMC-Na suspension of 10 ⁇ L per gram of body weight, 2.5 mg of crizotinib/kg of body weight In the group, 10 ⁇ L per gram
- the two separate administration groups of chidamide 10 mg/kg body weight and crizotinib 25 mg/kg body weight had the final effect on nude mice.
- the tumor-bearing volume of mice has a certain inhibition, and the final tumor inhibition rate of the combined drug group is higher than the sum of the tumor inhibition rates of the two single-agent groups, indicating that the two drugs have synergistic anti-tumor activity in HCC827 tumor-bearing nude mice.
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Abstract
Description
Claims (18)
- 一种含西达本胺的抗肿瘤药物组合物,其特征在于:它含有西达本胺和细胞间质上皮转换因子(cellular-mesenchymal epithelial transition factor,c-Met)抑制剂。
- 一种含西达本胺的抗肿瘤药物组合物,其特征在于:它含有西达本胺和间变性淋巴瘤激酶(anaplastic lymphoma kinase,ALK)抑制剂。
- 一种含西达本胺的抗肿瘤药物组合物,其特征在于:它含有西达本胺和repressor ofsilencing 1(ROS1)抑制剂。
- 根据权利要求1所述的药物组合物,其特征在于:所述c-Met抑制剂包括而不限于crizotinib、cabozantinib、tivantinib、glumetinib等具有c-Met抑制活性的药物。
- 根据权利要求2所述的药物组合物,其特征在于:所述ALK抑制剂包括而不限于ceritinib、alectinib、crizotinib、brigatinib、repotrectinib、entrectinib、lorlatinib等具有ALK抑制活性的药物。
- 根据权利要求3所述的药物组合物,其特征在于:所述ROS1抑制剂包括而不限于crizotinib、brigatinib、repotrectinib、entrectinib、lorlatinib等具有ROS1抑制活性的药物。
- 根据权利要求1或4所述的药物组合物,其特征在于:所述西达本胺和c-Met抑制剂的重量比为1∶1~1∶5。
- 根据权利要求2或5所述的药物组合物,其特征在于:所述西达本胺和ALK抑制剂的重量比为1∶1~1∶5。
- 根据权利要求3或6所述的药物组合物,其特征在于:所述西达本胺和ROS1抑制剂的重量比为1∶1~1∶5。
- 根据权利要求1~9任一项所述的药物组合物,其特征在于:还包含药学上可接受的载体。
- 权利要求1~10任一项所述的药物组合物在制备治疗c-Met或ALK或ROS发生基因扩增、基因重排、基因过表达或其他基因突变等的恶性肿瘤的药物中的用途。
- 根据权利要求11所述的用途,其特征在于:所述恶性肿瘤包括而不限于肺癌、胃癌、肝癌、乳腺癌、皮肤癌、肠癌、卵巢癌、胰腺癌、淋巴瘤、神经母细胞瘤。
- 一种药盒,其特征在于:它含有权利要求1~10任一项所述的药物组合物。
- 根据权利要求13所述的药盒,其特征在于:所述西达本胺与c-Met抑制剂、ALK抑制剂或ROS1抑制剂分别是具有相同或不同规格的单位制剂。
- 根据权利要求13~14任一项所述的药盒,其特征在于:所述西达本胺与c-Met抑制剂、ALK抑制剂或ROS1抑制剂分别置于单独容器中提供。
- 根据权利要求13~15任一项所述的药盒,其特征在于:所述西达本胺分别与c-Met抑制剂、ALK抑制剂或ROS1抑制剂的重量比为1∶1~1∶5。
- 一种治疗恶性肿瘤的方法,其特征在于:包括向有需要的患者施用治疗有效量的权利要求1~10任一项的药物组合物或权利要求13~16任一项所述的药盒的步骤。
- 根据权利要求17所述的方法,其特征在于:所述西达本胺与c-Met抑制剂、ALK抑制剂或ROS1抑制剂同时、分别或依次给药。
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CN115322171A (zh) * | 2022-08-30 | 2022-11-11 | 深圳微芯生物科技股份有限公司 | 一种trka(g667c)和flt3靶点抑制剂及其与西达本胺的组合物 |
WO2023193705A1 (zh) * | 2022-04-07 | 2023-10-12 | 深圳微芯生物科技股份有限公司 | 西奥罗尼在抗胰腺癌中的用途 |
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WO2023193705A1 (zh) * | 2022-04-07 | 2023-10-12 | 深圳微芯生物科技股份有限公司 | 西奥罗尼在抗胰腺癌中的用途 |
CN115322171A (zh) * | 2022-08-30 | 2022-11-11 | 深圳微芯生物科技股份有限公司 | 一种trka(g667c)和flt3靶点抑制剂及其与西达本胺的组合物 |
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