Targeting cancer with small-molecule pan-KRAS degraders
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.
Authors
- Johannes Popow (ORCID: https://orcid.org/0000-0002-1093-0936)
- Andre J. Wijaya (ORCID: https://orcid.org/0009-0006-0378-376X)
- Christiane Kofink
- Jake Goodwin‐Tindall
- Eva Strauss
- Emelyne Diers (ORCID: https://orcid.org/0000-0001-5951-7918)
- Arnel A. Lauber (ORCID: https://orcid.org/0000-0002-2949-728X)
- William Farnaby (ORCID: https://orcid.org/0000-0001-8610-932X)
- Melanie Wurm (ORCID: https://orcid.org/0000-0002-2317-6952)
- Georg Boeck (ORCID: https://orcid.org/0009-0002-0409-5783)
- Andreas Gollner (ORCID: https://orcid.org/0000-0002-4347-8296)
- Sabine Olt
- Alessio Ciulli (ORCID: https://orcid.org/0000-0002-8654-1670)
- Gerhard W. Fischer (ORCID: https://orcid.org/0000-0001-9861-1528)
- Vesna Vetma (ORCID: https://orcid.org/0000-0003-4013-6917)
- Harald Weinstabl (ORCID: https://orcid.org/0000-0003-1308-2730)
- Ross McLennan (ORCID: https://orcid.org/0000-0001-8125-7702)
- Claire Whitworth (ORCID: https://orcid.org/0000-0003-3174-7652)
- Polina Prokofeva (ORCID: https://orcid.org/0000-0001-9528-2204)
- Heribert Arnhof
- David Zollman (ORCID: https://orcid.org/0000-0002-7613-2013)
- Bernhard Küster (ORCID: https://orcid.org/0000-0002-9094-1677)
- Daniel Peter (ORCID: https://orcid.org/0000-0003-1156-1033)
- Jens Quant (ORCID: https://orcid.org/0009-0005-6816-0160)
- Vanessa Roessler
- Roland Kousek
- Manfred Koegl (ORCID: https://orcid.org/0000-0001-6633-9769)
- Oliver Petermann
- Peter Ettmayer (ORCID: https://orcid.org/0000-0002-8422-2625)
- Siying Zhong (ORCID: https://orcid.org/0000-0003-1142-7889)
- Patrick Strack
- Nicole Trainor (ORCID: https://orcid.org/0000-0002-3758-9969)
- Carina Hasenoehrl
- Nikolai Mischerikow
- Silvia Arce-Solano (ORCID: https://orcid.org/0000-0003-4357-3661)
- Peggy Stolt-Bergner (ORCID: https://orcid.org/0000-0002-5887-2915)
- Aileen B. Frost (ORCID: https://orcid.org/0009-0009-8897-0290)
- Jale Karolyi‐Oezguer
- Katrin Kropatsch
- Shakil Khan
- Barbara Kratochvil
- Sammy Bell (ORCID: https://orcid.org/0009-0001-4272-8441)
- Theresa Klawatsch
Institutions
- University of Dundee (GB)
- Boehringer Ingelheim (Austria) (AT)
- Boehringer Ingelheim (United States) (US)
- Technical University of Munich (DE)
Publication Details
- Journal
- Science
- Published
- 2024-09-19
- DOI
- https://doi.org/10.1126/science.adm8684
- Citations
- 141
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 32.97
Funders
- University of Dundee
- Wellcome Trust
- Medical Research Council