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Discovery of MK-1084: An Orally Bioavailable and Low-Dose KRAS G12C Inhibitor.

Xiaoshen MaDavid L SlomanRuchia DuggalKenneth D AndersonJeanine E BallardIndu BharathanChristopher BrynczkaSymon GathiakaTimothy J HendersonThomas W LyonsRichard MillerErik V MunsellPeter OrthRyan D OtteAnandan PalaniDanica A RankicMichelle R RobinsonAaron C SatherNicolas SolbanXuelei Sherry SongXin WenZangwei XuYi YangRuojing YangPhil J DayAlexander StoeckDavid Jonathan BennettYongxin Han
Published in: Journal of medicinal chemistry (2024)
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.
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