Small molecular compound with antagonism of PD-1/PD-L1 interaction and application of small molecular compound

A small molecule compound, PD-L1 technology, applied in the field of anti-tumor drug development and application, can solve the problem of not providing further in vivo activity characterization, and achieve low liver and kidney toxicity, good application prospects, and broad anti-cancer effects

Inactive Publication Date: 2021-01-08
LANZHOU UNIVERSITY
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Problems solved by technology

At present, a class of small molecule inhibitors with better targeting activity and clear mechanism of action are reported by BMS, however, no further in vivo activity characterization is provided, including the efficacy and safety of these small molecules

Method used

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  • Small molecular compound with antagonism of PD-1/PD-L1 interaction and application of small molecular compound
  • Small molecular compound with antagonism of PD-1/PD-L1 interaction and application of small molecular compound
  • Small molecular compound with antagonism of PD-1/PD-L1 interaction and application of small molecular compound

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Embodiment Construction

[0029] The present invention will be further described below through specific examples, but it should not be understood that the scope of the above subject of the present invention is limited to the following examples. All technologies realized based on the above content of the present invention belong to the scope of the present invention.

[0030] In the present invention, based on the crystal structure (5J89) of the complex of hPD-L1 and small molecule BMS-202, the applicant used Schrödinger software ( LLC, New York, United States, 2015) carried out the screening and molecular docking of small molecule pharmacophores from the Specs compound library, selected the advantageous structure of docking for experimental verification, and finally screened out the CBPA small molecule compound of the present invention (SPECS No. .AN-465 / 42833793) has good hPD-1 / hPD-L1 inhibitory activity. The applicant commissioned Shanghai Taosu Biochemical Technology Co., Ltd. to synthesize the sm...

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Abstract

The invention relates to an anti-tumor small-molecule inhibitor with a brand-new skeleton structure and targeting PD1/PDL1 interaction discovered on the basis of a virtual screening strategy and application of the anti-tumor small-molecule inhibitor. The small-molecule inhibitor N-{4-[(4-chlorobenzyl) oxy] benzyl}-N-(4-pyridinzyl) amine provided by the invention has good affinity and good biological activity with PD-L1, and can activate the immune response of T cells by inhibiting the interaction of PD-1/PD-L1 at the cell and animal level, so as to effectively target and kill tumor cells and block the immune escape way of tumor cells. In addition, the small molecule inhibitor has no obvious toxic or side effect. Therefore, the small molecule inhibitor can be effectively used for treating cancer diseases, can be used for treating tumors such as melanoma, colon cancer, gastric cancer, breast cancer, liver cancer and lung cancer, has important clinical value and has a wide development prospect.

Description

Technical field: [0001] The invention belongs to the technical field of research and development and application of antitumor drugs, and relates to a small molecule inhibitor with PD-1 / PD-L1 inhibitory activity and its application. Background technique: [0002] With the continuous development at the molecular level, immune checkpoint blockade is an advanced strategy that has been gradually discovered and has rapidly developed into the most promising cancer immunotherapy. Among them, PD-1 / PD-L1 inhibitors have fully demonstrated their advantages in various tumor treatment fields. [0003] PD-1 (CD279) is a cell surface receptor mainly expressed on activated T cells, B cells, monocytes, and natural killer T cells. Its two known naturally occurring ligands are PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273). PD-L1 is constitutively expressed by macrophages, B cells, activated T cells and parenchymal cells and is upregulated in many types of tumors. In tumors, when PD-1 binds ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/38A61K31/4409A61P35/00
CPCC07D213/38A61P35/00
Inventor 姚小军王凤玲朱永昌韩建庭刘焕香
Owner LANZHOU UNIVERSITY
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