Pan-KRAS inhibitor disables oncogenic signalling and tumour growth

Dongsung Kim, Lorenz Herdeis, Dorothea Rudolph, Yulei Zhao, Jark Böttcher, Alberto Vides, Carlos I. Ayala-Santos, Yasin Pourfarjam, Antonio Cuevas-Navarro, Jenny Y. Xue, Andreas Mantoulidis, Joachim Bröker, Tobias Wunberg, Otmar Schaaf, Johannes Popow, Bernhard Wolkerstorfer, Katrin Gabriele Kropatsch, Rui Qu, Elisa Stanchina, Ben Sang, Chuanchuan Li, Darryl B. McConnell, Norbert Kraut and Piro Lito ()
Additional contact information
Dongsung Kim: Memorial Sloan Kettering Cancer Center
Lorenz Herdeis: Boehringer Ingelheim
Dorothea Rudolph: Boehringer Ingelheim
Yulei Zhao: Memorial Sloan Kettering Cancer Center
Jark Böttcher: Boehringer Ingelheim
Alberto Vides: Memorial Sloan Kettering Cancer Center
Carlos I. Ayala-Santos: Memorial Sloan Kettering Cancer Center
Yasin Pourfarjam: Memorial Sloan Kettering Cancer Center
Antonio Cuevas-Navarro: Memorial Sloan Kettering Cancer Center
Jenny Y. Xue: Memorial Sloan Kettering Cancer Center
Andreas Mantoulidis: Boehringer Ingelheim
Joachim Bröker: Boehringer Ingelheim
Tobias Wunberg: Boehringer Ingelheim
Otmar Schaaf: Boehringer Ingelheim
Johannes Popow: Boehringer Ingelheim
Bernhard Wolkerstorfer: Boehringer Ingelheim
Katrin Gabriele Kropatsch: Boehringer Ingelheim
Rui Qu: Memorial Sloan Kettering Cancer Center
Elisa Stanchina: Memorial Sloan Kettering Cancer Center
Ben Sang: Memorial Sloan Kettering Cancer Center
Chuanchuan Li: Memorial Sloan Kettering Cancer Center
Darryl B. McConnell: Boehringer Ingelheim
Norbert Kraut: Boehringer Ingelheim
Piro Lito: Memorial Sloan Kettering Cancer Center

Nature, 2023, vol. 619, issue 7968, 160-166

Abstract: Abstract KRAS is one of the most commonly mutated proteins in cancer, and efforts to directly inhibit its function have been continuing for decades. The most successful of these has been the development of covalent allele-specific inhibitors that trap KRAS G12C in its inactive conformation and suppress tumour growth in patients1–7. Whether inactive-state selective inhibition can be used to therapeutically target non-G12C KRAS mutants remains under investigation. Here we report the discovery and characterization of a non-covalent inhibitor that binds preferentially and with high affinity to the inactive state of KRAS while sparing NRAS and HRAS. Although limited to only a few amino acids, the evolutionary divergence in the GTPase domain of RAS isoforms was sufficient to impart orthosteric and allosteric constraints for KRAS selectivity. The inhibitor blocked nucleotide exchange to prevent the activation of wild-type KRAS and a broad range of KRAS mutants, including G12A/C/D/F/V/S, G13C/D, V14I, L19F, Q22K, D33E, Q61H, K117N and A146V/T. Inhibition of downstream signalling and proliferation was restricted to cancer cells harbouring mutant KRAS, and drug treatment suppressed KRAS mutant tumour growth in mice, without having a detrimental effect on animal weight. Our study suggests that most KRAS oncoproteins cycle between an active state and an inactive state in cancer cells and are dependent on nucleotide exchange for activation. Pan-KRAS inhibitors, such as the one described here, have broad therapeutic implications and merit clinical investigation in patients with KRAS-driven cancers.

Date: 2023
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DOI: 10.1038/s41586-023-06123-3

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