Targeting cancer with small-molecule pan-KRAS degraders

• 成果类型: Article
• 署名作者: Popow, Johannes; Farnaby, William; Gollner, Andreas; Kofink, Christiane; Fischer, Gerhard; Wurm, Melanie; Zollman, David; Wijaya, Andre; Mischerikow, Nikolai; Hasenoehrl, Carina; Prokofeva, Polina; Arnhof, Heribert; Arce-Solano, Silvia; Bell, Sammy; Boeck, Georg; Diers, Emelyne; Frost, Aileen B.; Goodwin-Tindall, Jake; Karolyi-Oezguer, Jale; Khan, Shakil; Klawatsch, Theresa; Koegl, Manfred; Kousek, Roland; Kratochvil, Barbara; Kropatsch, Katrin; Lauber, Arnel A.; Mclennan, Ross; Olt, Sabine; Peter, Daniel; Petermann, Oliver; Roessler, Vanessa; Stolt-Bergner, Peggy; Strack, Patrick; Strauss, Eva; Trainor, Nicole; Vetma, Vesna; Whitworth, Claire; Zhong, Siying; Quant, Jens; Weinstabl, Harald; Kuster, Bernhard; Ettmayer, Peter; Ciulli, Alessio
• 署名单位: Boehringer Ingelheim; University of Dundee; University of Dundee; Technical University of Munich; Boehringer Ingelheim
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-10758
• DOI: 10.1126/science.adm8684
• 发表日期: 2024-09-20
• 页码: 1338-1347
• 关键词: e3 ubiquitin ligase; potent; optimization; inhibitor

摘要

Mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein are highly prevalent in cancer. However, small-molecule concepts that address oncogenic KRAS alleles remain elusive beyond replacing glycine at position 12 with cysteine (G12C), which is clinically drugged through covalent inhibitors. Guided by biophysical and structural studies of ternary complexes, we designed a heterobifunctional small molecule that potently degrades 13 out of 17 of the most prevalent oncogenic KRAS alleles. Compared with inhibition, KRAS degradation results in more profound and sustained pathway modulation across a broad range of KRAS mutant cell lines, killing cancer cells while sparing models without genetic KRAS aberrations. Pharmacological degradation of oncogenic KRAS was tolerated and led to tumor regression in vivo. Together, these findings unveil a new path toward addressing KRAS-driven cancers with small-molecule degraders.