Targeting cancer with small-molecule pan-KRAS degraders

• Published in: Science (American Association for the Advancement of Science) Vol. 385; no. 6715; pp. 1338 - 1347
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 20.09.2024
• Subjects: Alleles; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cancer; Cell Line, Tumor; Chimeras; Drug delivery; Drug development; Glycine; Humans; K-Ras protein; Mice; Mutation; Neoplasms - drug therapy; Neoplasms - genetics; Proteolysis; Proteolysis Targeting Chimera - chemistry; Proteolysis Targeting Chimera - pharmacology; Proteolysis Targeting Chimera - therapeutic use; Proto-Oncogene Proteins p21(ras) - antagonists & inhibitors; Proto-Oncogene Proteins p21(ras) - chemistry; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; Regression analysis; Sarcoma; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Small Molecule Libraries - therapeutic use; Tumors; Ubiquitin-protein ligase
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.adm8684

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.