Abstract B074: Discovery of MK-1084, a low dose selective clinical stage KRAS G12C inhibitor

Abstract

Abstract KRAS mutations are the predominant oncogenic drivers in multiple indications including non-small cell lung carcinoma (NSCLC), colorectal carcinoma (CRC) and pancreatic ductal adenocarcinoma (PDAC). KRAS has long been considered a challenging target due to the perceived lack of druggable binding pockets and high flexibility of the protein. However, recent progress in discovering and developing covalent inhibitors against the GDP-loaded form of G12C mutant KRAS has provided a strategy for targeting mutant-specific KRAS as the cysteine residue in the switch II pocket offers a handle for covalent modification. With encouraging efficacy data observed with KRAS G12C-GDP covalent inhibitors in the clinic, attention has shifted to increasing response rate and durability of response. Achieving these goals will likely require combination therapies with different mechanisms of action such as PD-1 or EGFR inhibitors, or other inhibitors within the MAPK pathway (e.g. MEKi, SHP2i). Excellent tolerability of a KRAS G12C inhibitor in such combination settings will be a pre-requisite to success of this strategy. In 2019, Merck & Co., Inc., entered into a research collaboration and license agreement with Taiho Pharmaceutical Co, Ltd. and Astex Pharmaceuticals (UK), to research, develop and commercialize small molecule modulators of mutant KRAS oncogenes, including MK-1084, an inhibitor of G12C-GDP which was advanced under the collaboration. MK-1084 is a highly potent and specific KRAS G12C-GDP macrocyclic inhibitor that was discovered from a structure-guided lead optimization effort. It exhibits a favorable preclinical potency, PK, PK/PD, efficacy, off-target and tolerability profile and has QD oral dosing potential with a projected clinical dose that compares favorably to approved competitors. The significantly lower dose projection along with superior off-target profile puts MK-1084 in a position to differentiate in the clinic regarding dose/pill burden, potential for drug-drug interactions (DDIs) and/or risks associated with drug induced liver injury (DILI) in a combination setting. MK-1084 is currently being evaluated in the clinic for solid tumors as a monotherapy and in combination with pembrolizumab. We will describe the research efforts that led to the discovery of MK-1084, its pre-clinical profile, and disclose its structure. Citation Format: Matthew L Maddess, David L Sloman, Xiaoshen Ma, Anandan Palani, Alexander Stoeck, Aaron C Sather, Nicolas Solban, Ruchia Duggal, Jeanine Ballard, Erik V Munsell, Lin-Chi Chen, Yongxin Han, Richard Miller, Symon Gathiaka, Christopher Brynczka, Hongming Li, Ruojing Yang, Christopher Brynczka, Phil Day. Discovery of MK-1084, a low dose selective clinical stage KRAS G12C inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B074.