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 HanPublished 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.
Keyphrases
- low dose
- wild type
- clinical trial
- small molecule
- high dose
- endothelial cells
- high throughput
- open label
- genome wide
- transcription factor
- randomized controlled trial
- induced pluripotent stem cells
- copy number
- cancer therapy
- dna methylation
- gene expression
- emergency department
- drug induced
- double blind
- electronic health record
- genome wide identification