Polycyclic compounds and methods for targeted degradation of rapidly accelerated fibrosarcoma polypeptides

By developing bifunctional compounds containing the E3 ubiquitin ligase binding moiety and the target protein binding moiety, the problem of difficulty in targeting and regulating RAF proteins in the prior art has been solved, and selective degradation and inhibition of RAF proteins and their mutated forms have been achieved.

CN113164775BActive Publication Date: 2025-03-18ARVINAS OPERATIONS INC +1
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Patent Information

Application Number
CN201980073600.1
Authority / Receiving Office
CN · China
Patent Type
Patents(China)
Current Assignee / Owner
Priority Date
2018-09-07
Filing Date
2019-09-07
Publication Date
2025-03-18
Estimated Expiration
2039-09-07

AI Technical Summary

Technical Problem

The prior art is difficult to effectively target and regulate RAF proteins, especially their mutated forms, resulting in therapeutic difficulties.

Method used

Bifunctional compounds (PROTACs) are developed that contain the E3 ubiquitin ligase binding moiety and the target protein binding moiety, and the degradation and inhibition of the target protein is achieved by placing the target protein near the ubiquitin ligase.

Benefits of technology

Selective degradation and inhibition of RAF protein and its mutant forms are achieved, the impact on wild-type BRaf is avoided, and treatment plans for adversarial mutant types are provided.

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Abstract

The present disclosure relates to a bifunctional compound ULM-L-PTM, which can be used as a regulator of rapidly accelerated fibrosarcoma (RAF, such as c-RAF, A-RAF and / or B-RAF; target protein). Specifically, the present disclosure relates to a bifunctional compound, which contains a Von Hippel-Lindau, human cerebellin, inhibitor of apoptosis or mouse double minute homolog 2 ligand that binds to the corresponding E3 ubiquitin ligase on one end, and contains a portion that binds to the target protein RAF on the other end, so that the target protein is placed near the ubiquitin ligase to achieve degradation (and inhibition) of the target protein. The present disclosure exhibits a wide range of pharmacological activities related to degradation / inhibition of the target protein. The compounds and compositions of the present disclosure are used to treat or prevent diseases or conditions caused by aggregation or accumulation of the target protein or constitutive activation of the target protein.
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Claims

1. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

2. A pharmaceutical composition comprising an effective amount of the compound according to claim 1, and a pharmaceutically acceptable carrier.

3. Use of the compound according to claim 1, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 2 in the preparation of a medicament for treating a disease or condition associated with BRaf accumulation and aggregation, wherein the disease or condition associated with BRaf accumulation and aggregation is cancer.

4. The use according to claim 3, wherein the cancer is colorectal cancer, lung cancer or melanoma.

Citation Information

Patent Citations

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    US10723717B2

  • Compounds and methods for the enhanced degradation of targeted proteins

    US10730870B2

  • Compounds and methods for the targeted degradation of bromodomain-containing proteins

    US10772962B2

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