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

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 DC 50 and IC 50 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 KRAS G12V mutation. Additionally in an efficacy study with mice bearing SW1990 xenograft, at 10 mg/kg, qW, the compounds regressed the tumors by over 90%.