Targeting cancer with small-molecule pan-KRAS degraders

Johannes Popow(Boehringer Ingelheim (Austria)), William Farnaby(University of Dundee), Andreas Gollner(Boehringer Ingelheim (Austria)), Christiane Kofink(Boehringer Ingelheim (Austria)), Gerhard W. Fischer(Boehringer Ingelheim (Austria)), Melanie Wurm(Boehringer Ingelheim (Austria)), David Zollman(University of Dundee), Andre J. Wijaya(University of Dundee), Nikolai Mischerikow(Boehringer Ingelheim (Austria)), Carina Hasenoehrl(Boehringer Ingelheim (Austria)), Polina Prokofeva(Technical University of Munich), Heribert Arnhof(Boehringer Ingelheim (Austria)), Silvia Arce-Solano(Boehringer Ingelheim (Austria)), Sammy Bell(Boehringer Ingelheim (United States)), Georg Boeck(Boehringer Ingelheim (Austria)), Emelyne Diers(University of Dundee), Aileen B. Frost(University of Dundee), Jake Goodwin‐Tindall(University of Dundee), Jale Karolyi‐Oezguer(Boehringer Ingelheim (Austria)), Shakil Khan(University of Dundee), Theresa Klawatsch(Boehringer Ingelheim (Austria)), Manfred Koegl(Boehringer Ingelheim (Austria)), Roland Kousek(Boehringer Ingelheim (Austria)), Barbara Kratochvil(Boehringer Ingelheim (Austria)), Katrin Kropatsch(Boehringer Ingelheim (Austria)), Arnel A. Lauber(Boehringer Ingelheim (Austria)), Ross McLennan(University of Dundee), Sabine Olt(Boehringer Ingelheim (Austria)), Daniel Peter(Boehringer Ingelheim (Austria)), Oliver Petermann(Boehringer Ingelheim (Austria)), Vanessa Roessler(Boehringer Ingelheim (Austria)), Peggy Stolt-Bergner(Boehringer Ingelheim (Austria)), Patrick Strack(Boehringer Ingelheim (Austria)), Eva Strauss(Boehringer Ingelheim (Austria)), Nicole Trainor(University of Dundee), Vesna Vetma(University of Dundee), Claire Whitworth(University of Dundee), Siying Zhong(University of Dundee), Jens Quant(Boehringer Ingelheim (Austria)), Harald Weinstabl(Boehringer Ingelheim (Austria)), Bernhard Küster(Technical University of Munich), Peter Ettmayer(Boehringer Ingelheim (Austria)), Alessio Ciulli(University of Dundee)
Science
September 19, 2024
10.1126/science.adm8684
Cited by 152Open Access
Full Text

Abstract

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.

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