Discovery of Novel Oral Covalent Inhibitors Targeting Active GTP-Bound KRASG12C with Potent Antitumor Activity
Juan del Pozo, Elisabeth Hennessy, Patrick Schoepf, Kazuaki Shibata, Kei Akemoto, Naomi Abe, Christopher Agnew, Hiroki Asakura, David Jonathan Bennett, Samantha A. Burgess, Xiaomei Chai, Gianni Chessari, Philip J. Day, Ruchia Duggal, George M. Giambasu, Christopher C. F. Hamlett, Yuan Jiang, Taiki Kida, Toshiharu Komori, Hitomi Kondo, Brian M. Lacey, Todd W. Mayhood, Risako Miura, Shinji Mizuarai, Erik V. Munsell, Marc O’Reilly, Barbara Rath, David C. Rees, Michael C. Ryan, Takeshi Sagara, Toshihiro Sakamoto, Jordan De Jesus Silva, Nicolas Solban, Xuelei Sherry Song, Tetsuya Sugimoto, Miki Terasaka, David G. Twigg, Hiroyuki Ueno, Kentaro Wakayama, Zangwei Xu, Tomohiro Yamamoto, Alexander Stoeck, Yongxin HanAbstract
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.