Identification and characterization of binders to a cryptic and functional pocket in KRAS

Kim S. Beyer, Jessica Klein, Stéphanie Katz, Patrick Welker, Mylene Lanter, Daniel Guthy, Kerstin Pollehn, Aurélie Gluck-Gadé, Melusine Bleu, Jessica Desogus, Marc Hattenberger, Damiano Borrello, Wassim Abdul Rahman, Florence Zink, Nils Ostermann, Wolfgang Jahnke, Christoph E. Dumelin, Lukas Leder, Oliver Esser, Lionel Muller, Andreas Marzinzik, Regis Cébé, Kathrin Müller, Giorgio G. Galli, Luca Tordella, Simona Cotesta, Saskia M. Brachmann and Sauveur-Michel Maira ()
Additional contact information
Kim S. Beyer: Novartis Biomedical Research
Jessica Klein: Novartis Biomedical Research
Stéphanie Katz: Novartis Biomedical Research
Patrick Welker: Novartis Biomedical Research
Mylene Lanter: Novartis Biomedical Research
Daniel Guthy: Novartis Biomedical Research
Kerstin Pollehn: Novartis Biomedical Research
Aurélie Gluck-Gadé: Novartis Biomedical Research
Melusine Bleu: Novartis Biomedical Research
Jessica Desogus: Novartis Biomedical Research
Marc Hattenberger: Novartis Biomedical Research
Damiano Borrello: Novartis Biomedical Research
Wassim Abdul Rahman: Novartis Biomedical Research
Florence Zink: Novartis Biomedical Research
Nils Ostermann: Novartis Biomedical Research
Wolfgang Jahnke: Novartis Biomedical Research
Christoph E. Dumelin: Novartis Biomedical Research
Lukas Leder: Novartis Biomedical Research
Oliver Esser: Novartis Biomedical Research
Lionel Muller: Novartis Biomedical Research
Andreas Marzinzik: Novartis Biomedical Research
Regis Cébé: Novartis Biomedical Research
Kathrin Müller: Novartis Biomedical Research
Giorgio G. Galli: Novartis Biomedical Research
Luca Tordella: Novartis Biomedical Research
Simona Cotesta: Novartis Biomedical Research
Saskia M. Brachmann: Novartis Biomedical Research
Sauveur-Michel Maira: Novartis Biomedical Research

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract RAS proteins control cell proliferation and activating mutations are collectively the most frequent oncogenic event observed in cancer patients, justifying investments into multiple drug discovery efforts. While RAS-directed therapeutic agents targeting either the inactive GDP-bound or the active GTP-bound state have entered the clinic, invariably resistance is observed. Mutations at drug binding sites represent a common resistance mechanism indicating the need to discover new targetable pockets in RAS. Such efforts are hindered by the small globular size of the protein, for long considered undruggable. Here we perform macrocyclic peptides mRNA and nanobody yeast display screens and discover a targetable ligand-induced pocket in RAS. In vitro and cellular experiments with the KM12 and KM12-AM nanobodies show RAS inhibition via displacement of cRAF, by affecting their protein-protein interaction via the less studied cRAF CRD domain. Further, we provide orthogonal functional validation for the discovered binding pocket via mutagenesis experiments. Notably, the discovered RAS-targeting approach enables simultaneous targeting of both GTP-bound active and GDP-bound inactive states and leaves the SwII pocket unaltered, opening possibilities of combinatorial approaches with clinically approved SwII pocket inhibitors.

Date: 2025
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DOI: 10.1038/s41467-025-65844-3

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