Discovery of MK-1084: An Orally Bioavailable and Low-Dose KRASG12C Inhibitor

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 KRASG12C 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.

RAS基因（RAS gene）的致癌突变占所有人类肿瘤的30%，其中超过60%为位于热点密码子12的KRAS突变。经过数十年的深入研究攻关，共价抑制策略已实现对这一此前被视为"不可成药"靶点的选择性靶向。本文披露了MK-1084的研发历程：MK-1084是一款口服生物可利用、低剂量的KRASG12C共价抑制剂，目前正处于I期临床试验阶段（临床试验编号：NCT05067283）。本研究通过基于结构的药物设计方法鉴定出大环核心结构，并通过基于假说的生物制药特性优化，进一步提升了其代谢稳定性与耐受性。