Discovery of Novel Oral Covalent Inhibitors Targeting Active GTP-Bound KRASG12C with Potent Antitumor Activity

Abstract Current KRASG12C inhibitors mainly target the inactive GDP-bound state, but clinical efficacy is limited, and resistance mechanisms have been identified. We disclose novel covalent inhibitors that selectively target the active GTP-bound KRASG12C. Starting from a high-throughput screen, we identified a keto-indolizine scaffold featuring an aniline-derived acrylamide warhead that covalently binds Cys12 in the switch-II pocket of active KRASG12C. X-ray crystallography revealed key interactions of acrylamide with GMPPCP′s γ-phosphate, stabilizing the GTP state. We present medicinal chemistry efforts leading to the discovery of compound 17, which shows favorable oral bioavailability in preclinical species, exhibiting prolonged disruption of the KRAS-cRAF interaction and downstream ERK phosphorylation in vivo. In a KRASG12C-driven pancreatic cancer xenograft model (MIA PaCa-2), orally administered compound 17 achieved complete tumor regression for up to 45 days with good tolerability. This study establishes a novel class of KRASG12C inhibitors targeting the active GTP-bound state, which may have the potential to overcome some resistance mechanisms.

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Publication Details

Journal
Journal of Medicinal Chemistry
Published
2026-09-24
DOI
https://doi.org/10.1021/acs.jmedchem.6c01318
Primary Topic
Protein Kinase Regulation and GTPase Signaling
Type
article
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Discovery of Novel Oral Covalent Inhibitors Targeting Active GTP-Bound KRASG12C with Potent Antitumor Activity

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Journal of Medicinal Chemistry
Protein Kinase Regulation and GTPase Signaling
article

Discovery of Novel Oral Covalent Inhibitors Targeting Active GTP-Bound KRASG12C with Potent Antitumor Activity

Alexander Stoeck, Brian M. Lacey, Gianni Chessari, Nicolas Solban, Kei Akemoto, Xuelei S. Song, Christopher Agnew, Shinji Mizuarai, David Jonathan Bennett, Zangwei Xu, David C. Rees, Juan del Pozo, Ruchia Duggal, Toshiharu Komori, George M. Giambaşu, Samantha A. Burgess, Kentaro Wakayama, Elisabeth T. Hennessy, Erik V. Munsell, Yuan Jiang, Naomi Abe, Hiroyuki Ueno, Jordan De Jesus Silva, Todd Mayhood, Christopher C. F. Hamlett, Xiaomei Chai, Tetsuya Sugimoto, David G. Twigg, Takeshi Sagara, Marc O’Reilly, Yongxin Han, Michael C. Ryan, Taiki Kida, Kazuaki SHIBATA, Barbara Rath, Philip J. Day, Hitomi Kondo, Risako Miura, Hiroki Asakura, Toshihiro Sakamoto, Miki Terasaka, Patrick Schoepf, Tomohiro Yamamoto
article en

Abstract

Abstract Current KRASG12C inhibitors mainly target the inactive GDP-bound state, but clinical efficacy is limited, and resistance mechanisms have been identified. We disclose novel covalent inhibitors that selectively target the active GTP-bound KRASG12C. Starting from a high-throughput screen, we identified a keto-indolizine scaffold featuring an aniline-derived acrylamide warhead that covalently binds Cys12 in the switch-II pocket of active KRASG12C. X-ray crystallography revealed key interactions of acrylamide with GMPPCP′s γ-phosphate, stabilizing the GTP state. We present medicinal chemistry efforts leading to the discovery of compound 17, which shows favorable oral bioavailability in preclinical species, exhibiting prolonged disruption of the KRAS-cRAF interaction and downstream ERK phosphorylation in vivo. In a KRASG12C-driven pancreatic cancer xenograft model (MIA PaCa-2), orally administered compound 17 achieved complete tumor regression for up to 45 days with good tolerability. This study establishes a novel class of KRASG12C inhibitors targeting the active GTP-bound state, which may have the potential to overcome some resistance mechanisms.

Journal of Medicinal Chemistry
Merck & Co., Inc., Rahway, NJ, USA (United States) (US), Taiho Pharmaceutical (Japan) (JP)
Decent work and economic growth
Openalex Percentile: Top 19%
Protein Kinase Regulation and GTPase Signaling
DOISourceOpenAlex
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