From KRAS G12D to Pan-KRAS Inhibitors─A Journey Enabled by Synthetic Innovation and Structure-Based Drug Design

Journal of Medicinal Chemistry 2026

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Authors: Xiaoshen Ma, David L. Sloman, Timothy J. Henderson, David Jonathan Bennett, Gianni Chessari, Philip J. Day, Ruchia Duggal, Emma K. Edelstein, Symon M. Gathiaka, Andrew J. Hoover, Steven Howard, Shuhei Kawamura
+24 more Yu Kobayakawa, Brian M. Lacey, Thomas W. Lyons, My Sam Mansueto, Richard D. Miller, Shinji Mizuarai, Erik V. Munsell, Marc O’Reilly, Tsuyoshi Oshima, Ryan D. Otte, Anandan Palani, DC Rees, Takeshi Sagara, Aaron C. Sather, Patrick Schöpf, Kazuaki SHIBATA, Yuki Shikata, Nicolas Solban, Sriraman Venkataraman, Dan Su, Uma Swaminathan, Yingchun Ye, Alexander Stoeck, Yongxin Han
DOI: 10.1021/acs.jmedchem.5c03662
Cited by: 1
References: 29

Abstract

KRAS, a significant oncology target, has been challenging to develop drugs for until recent discoveries of KRAS G12C mutant-specific covalent inhibitors, including MK-1084. This article describes efforts toward the discovery of KRAS G12D mutant-specific inhibitors and how synthetic innovations and structure-based drug design were utilized to facilitate the discovery of pan-KRAS inhibitors.

Fields of Study & Subjects

Protein Kinase Regulation and GTPase Signaling Receptor Mechanisms and Signaling PI3K/AKT/mTOR signaling in cancer

Publication details

Journal / source
Journal of Medicinal Chemistry
Publisher
American Chemical Society (ACS)
Volume
69
Issue
8
Pages
9215–9241
Publication date
9 April 2026
Language
EN