Discovery of MK-1084: An Orally Bioavailable and Low-Dose KRAS<sup>G12C</sup> Inhibitor
Xiaoshen Ma, David L. Sloman, Ruchia Duggal, Kenneth D. Anderson, Jeanine Ballard, Indu Bharathan, Christopher Brynczka, Symon Gathiaka, Timothy J. Henderson, Thomas W. Lyons, Richard Miller, Erik V. Munsell, Peter Orth, Ryan D. Otte, Anandan Palani, Danica A. Rankic, Michelle Robinson, Aaron C. Sather, Nicolas Solban, Xuelei S. Song, Xin Wen, Zangwei Xu, Yi Yang, Ruojing Yang, Phil Day, Alexander Stoeck, David Jonathan Bennett, Yongxin Han
Abstract
Oncogenic mutations in the RAS gene account for 30% of all human tumors; more than 60% of which present as KRAS mutations at the hotspot codon 12. After decades of intense pursuit, a covalent inhibition strategy has enabled selective targeting of this previously “undruggable” target. Herein, we disclose our journey toward the discovery of MK-1084, an orally bioavailable and low-dose KRAS G12C covalent inhibitor currently in phase I clinical trials (NCT05067283). We leveraged structure-based drug design to identify a macrocyclic core structure, and hypothesis-driven optimization of biopharmaceutical properties to further improve metabolic stability and tolerability.