Abstract 5151: Design and synthesis of highly efficacious CRBN-based pan-KRAS degraders targeting cancers with KRAS G12D, G12V and G12C mutations

Abstract Oncogenic mutation of KRAS is one of the most promising targets for cancer. Treatment with inhibitors inevitably lead to rapid onset of resistance, and loss of therapeutic effect after months. KRAS PROTACs may offer superior efficacy by eliminating mutated protein, disrupting scaffolding function and activating immune response, thus overcoming the rapid development of resistance. Using new E3 ligands developed in house, our compounds achieved less than 1 nM DC50 and IC50 in in vitro assays with G12D, G12V and G12C mutated cell lines. They exhibited excellent pharmacokinetic and pharmacodynamic properties in mice, and outstanding pharmacokinetic in rats, dogs, and monkeys. At 10 mg/kg, qW, the compounds achieved a remarkable TGI of over 92% in SW620 xenograft, a robust and challenging model of KRASG12V mutation. Additionally in an efficacy study with mice bearing SW1990 xenograft, at 10 mg/kg, qW, the compounds regressed the tumors by over 90%. Citation Format: Changwei Wang, Prithwish Ghosh, Shicheng Jin, Longchuan Bai, Donna McEachern, Angelo Aguilar, Qiuxia Li, Bo Wen, DUXIN SUN, Shaomeng Wang. Design and synthesis of highly efficacious CRBN-based pan-KRAS degraders targeting cancers with KRAS G12D, G12V and G12C mutations abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5151.