ArticleJournal of medicinal chemistry2026
Discovery of Highly Efficacious CRBN-Based KRAS Degraders Targeting Cancers with KRAS G12D and G12V Mutations.
Article in Journal of medicinal chemistry, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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11 authors.
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Abstract
KRAS G12D and G12V mutants account for >50% of human cancers carrying a mutated KRAS protein, and targeting KRAS proteins by induced protein degradation represents an attractive cancer therapeutic strategy. Herein, we present the design, synthesis, and evaluation of PROTAC KRAS degraders using a novel cereblon ligand, which led to the discovery of CW-10201 as a promising KRAS degrader. CW-10201 effectively induced degradation of KRASG12D and KRASG12V mutants at low nanomolar concentrations in cells and attained IC50 values of 2-4 nM in inhibition of cell growth in cancer cell lines carrying KRASG12D or KRASG12V mutation. It demonstrated excellent pharmacokinetic and pharmacodynamic properties in mice. CW-10201 was capable of attaining tumor regression in the SW1990 KRASG12D mutated xenograft tumor model and effectively inhibited tumor growth in the SW620 KRASG12V xenograft tumor model in mice at well-tolerated doses. CW-10201 represents a promising KRASG12D and KRASG12V degrader for extensive evaluation and optimization for the treatment of human cancers.
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