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Hypoxia inducible factor (HIF)-2 alpha small-molecule inhibitor and use thereof

A small molecule inhibitor, HIF-2 technology, applied in the field of tumor

Active Publication Date: 2018-06-22
中国医科大学
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, there are few reports on HIF-2α inhibitors. Only Cho et al. found a small molecule PT2399 that can target and inhibit HIF-2α in pVHL-deficient renal cell carcinoma cells, but there is no HIF2 that has effects on other tumors such as breast cancer and ovarian cancer. -alpha inhibitor report

Method used

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  • Hypoxia inducible factor (HIF)-2 alpha small-molecule inhibitor and use thereof
  • Hypoxia inducible factor (HIF)-2 alpha small-molecule inhibitor and use thereof
  • Hypoxia inducible factor (HIF)-2 alpha small-molecule inhibitor and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] Example 1: Structure and Identification of HIF-2α Inhibitor

[0073] The applicant used the molecular simulation drug design software MOE to perform pharmacophore screening and molecular docking, and conducted experimental verification based on the final docking advantage structure, thereby screening out the HIF-2α inhibitor of the present invention, showing that pyrimidine[1,2-a] Compounds with pyridine as the core can act as HIF-2α inhibitors, but changes in the substituents on the core can lead to different targets, and the final clinical indications used for treatment may also be different. This type of compound has a higher affinity to the PAS region (such as figure 1 As shown, S=-10.1898). The applicant entrusted Topscience Co., Ltd. to synthesize the HIF-2α inhibitor. The structure of the HIF-2α inhibitor is as follows:

[0074]

[0075]

[0076] Detect the proton spectrum of this compound 1 (ComA), carbon spectrum, respectively as figure 2 and image ...

Embodiment 2

[0077] Example 2: Antitumor activity of HIF-2α inhibitors.

[0078] 1 Experimental materials

[0079] 1.1 Cells and Reagents

[0080]Human breast cancer cell MCF-7, human ovarian cancer cell OVCAR-3. DMEM, DMEM / F12 medium, 1640 medium, Trypsin-EDTA (0.05%); B27, protein maker, EGF, bFGF, fetal bovine serum (FBS), dimethylsulfoxide (DMSO), paclitaxel (PTX), Cisplatin (DDP), thiazolyl blue (MTT), cell proliferation / toxicity detection kit (Cell counting kit-8, CCK-8) rabbit anti-human HIF-1α monoclonal antibody; rabbit anti-human HIF-2α monoclonal antibody; RIPA cell lysate, Protease inhibitor cocktail, goat anti-rabbit IgG antibody secondary antibody,.

[0081] 2 Experimental methods

[0082] 2.1 Cell culture

[0083] Take out MCF-7 and OVCAR-3 cells from liquid nitrogen, melt them in a water bath at 37°C, centrifuge at 1000rpm for 5 minutes, remove the supernatant, add 1ml of DMEM medium with 10% fetal bovine serum for MCF-7 cells, and transfer the cell suspension into 25c...

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Abstract

The invention belongs to the field of diagnosis and treatment of tumors, and relates to a hypoxia inducible factor (HIF)-2 alpha small-molecule inhibitor and use thereof in treatment of breast cancer,ovarian cancer and other tumors. The small-molecule inhibitor is a compound shown in a formula (I) or stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs of the compound shown in the formula (I); the proliferation of tumor cells is inhibited mainly by inhibiting HIF-2 alpha protein; furthermore, the HIF-2 alpha small-molecule inhibitor can inhibit the growth of CSCs with high expression of HIF-2 alpha, and can be used as a new anti-tumor drug to completely remove tumors and stem cells, thus having a broad application prospect.

Description

technical field [0001] The invention belongs to the field of tumor diagnosis and treatment, and relates to a small molecule inhibitor of HIF-2α and its use in treating tumors such as breast cancer and ovarian cancer. Background technique [0002] Cancer (cancer) is a malignant tumor. Generally, normal cells in the body undergo abnormal cell differentiation and proliferation due to external stimuli, and their growth is out of control, and they are invasive and metastatic. Cancer stem cells (cancer stem cells, CSCs) are also known as "tumor initiating cells", and the existence of CSCs has been found in various tumors such as breast cancer and ovarian cancer. CSCs are the seeds of tumor occurrence and recurrence, have strong self-renewal ability and multi-directional differentiation potential, and are the root of tumor drug resistance. Because CSCs are in a dormant state, their ability to divide and proliferate is weak, but current radiotherapy and chemotherapy are mainly aime...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/519A61P35/00
CPCC07D471/04A61P35/00
Inventor 魏敏杰颜媛媛何苗刘一诺张丽雯
Owner 中国医科大学
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