Heterocyclic compound for inducing degradation of KRAS protein

Heterocyclic compounds targeting KRAS mutations via the ubiquitin-proteasome system degrade mutant KRAS proteins and inhibit wild-type KRAS gene amplification, addressing the limitations of current cancer treatments for KRAS-mutated cancers.

WO2025159142A1 Publication Date: 2025-07-31ASTELLAS PHARMA INC
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Patent Information

Application Number
PCT/JP2025/001994
Authority / Receiving Office
WO · WO
Patent Type
Applications
Current Assignee / Owner
Priority Date
2024-01-24
Filing Date
2025-01-23
Publication Date
2025-07-31

AI Technical Summary

Technical Problem

Current treatments for cancers with KRAS mutations, particularly G12C, G12D, G12V, and G13D mutations, are limited in efficacy, and there is a need for compounds that can effectively induce the degradation of mutant KRAS proteins and inhibit wild-type KRAS gene amplification.

Method used

Development of heterocyclic compounds that link to E3 ligases via a linker, promoting the ubiquitin-proteasome system to degrade mutant and wild-type KRAS proteins, including G12C, G12D, G12V, and G13D mutants, and inhibit KRAS with amplified wild-type KRAS gene.

Benefits of technology

The heterocyclic compounds effectively induce the degradation of mutant KRAS proteins and inhibit KRAS, offering potential therapeutic benefits for cancers with KRAS mutations, including pancreatic, lung, and colorectal cancers.

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Abstract

Provided is a compound useful as an active ingredient in a pharmaceutical composition for treating cancer.　The present inventors have examined a compound useful as an active ingredient in a pharmaceutical composition for cancer treatment, and have completed the present invention by finding that: a heterocyclic compound represented by formula (I) and formula (I-I) has excellent an action of inducing degradation of a mutant KRAS protein and a wild-type KRAS protein, and in particular, an action of inducing degradation of a KRAS protein having a G12C mutation, G12D mutation, G12V mutation, or G13D mutation; and said heterocyclic compound has mutant KRAS inhibition and the inhibitory activity of KRAS amplified by a wild-type KRAS gene, and in particular, inhibitory activity of KRAS having a G12C mutation, G12D mutation, G12V mutation, or G13D mutation. The heterocyclic compound according to the present invention or a salt thereof can be used as a therapeutic agent for cancer.
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