Pyrazole derivatives as PD-1 / PD-l1 interaction inhibitors

Novel pyrazole derivatives provide a cost-effective and safe solution to block PD-1/PD-L1 interactions, restoring anti-tumor immune responses and addressing the limitations of current immunotherapies by inhibiting PD-1/PD-L1 interactions effectively.

WO2025003429A1PCT designated stage expired Publication Date: 2025-01-02INST NAT DE LA SANTE & DE LA RECHERCHE MEDICALE (INSERM) +3
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Patent Information

Application Number
PCT/EP2024/068292
Authority / Receiving Office
WO · WO
Patent Type
Applications
Current Assignee / Owner
Priority Date
2023-06-30
Filing Date
2024-06-28
Publication Date
2025-01-02

AI Technical Summary

Technical Problem

Current immunotherapies for cancer, such as monoclonal antibodies targeting the PD-1/PD-L1 axis, are costly, have side effects, and limited by high production costs, necessitating the development of novel small molecules with high bioavailability and low toxicity to efficiently block PD-1/PD-L1 interactions and restore anti-tumor immune responses.

Method used

Development of novel pyrazole derivatives that act as PD-1/PD-L1 interaction inhibitors, capable of efficiently blocking PD-1/PD-L1 interactions, with high bioavailability, low production costs, and non-toxic properties, formulated into pharmaceutical compositions for oral or parenteral administration.

Benefits of technology

The pyrazole derivatives effectively restore anti-tumor immune responses, eradicating dormant tumor cells by inhibiting PD-1/PD-L1 interactions, offering a more cost-effective and safer alternative to existing immunotherapies for various cancers and related diseases.

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Abstract

The present application relates to pyrazole derivatives as PD-1 / PD-L1 interaction inhibitors. The applicants designed compounds of general formula (I), wherein R', R2, y3, R3, R4, R5, R6 and R7 are as defined herein, that are able to efficiently block PD-1 / PD-L1 interactions in order to restore anti-tumor immune responses of subjects and eradicate dormant tumor cells and any tumors in which PD-L1 is involved in immunoevasion. The applicants confirmed that these compounds blocked the PD-1 / PD-L1 interactions by carrying out physicochemical tests (MST, NanoDSF) and in vitro biological tests (FRET assay, Promega Blockade assay, T cell assay). These compounds had an affinity (Kd) of the order of pM that was higher than that of the antibody atezolizumab used in clinical use, and had a comparable or better IC50 than that observed with atezolizumab. Thus, the present invention also relates to a pharmaceutical composition comprising said compound(s) and their uses in the treatment of PD-1-PD-L1 interactions-related diseases (cancer, chronic inflammatory diseases, neurological diseases and chronic infections).
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Citation Information

Patent Citations

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