Targeting Multiple KRAS Mutations with High-Affinity Macrocyclic Inhibitors: From Discovery to Preclinical Validation

Journal of Medicinal Chemistry 2026 Open access

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Authors: Dean P. Phillips, Phil B. Alper, Charles Y. Cho, Dmitry Borkin, Dong Han, Sarah E. Kochanek, Agnes Vidal-Biggart, Ananda Herath, Jitendra Gurjar, Wenshuo Lu, Casey J. N. Mathison, John M. Nelson
+62 more Wei Pei, Shanshan Yan, Bao Ngoc Nguyen, Timothy Hoffman, Barun Okram, Truc N. Nguyen, Songchun Jiang, Brian T. Masick, Zhicheng Wang, Victor Nikulin, Hong Yin, Yu Chen, Jose Juarez, Yelena Sarkisova, Yong Jia, Vicki Zhou, Guoxun Liu, Xianzhong Liu, Min Lu, Brandon L. Taylor, Lang Huynh, Yu Wang, Reynand Pacoma, Janine Baaten, Kathryn Topolewski, Clifford Wright, Trish Nguyen, Deborah A. Knee, Qian Liu, Jun Liu, Jie Li, Cyrus Virata, Sergio Briones, Michael DiDonato, Badry Bursulaya, David Hugh Jones, Darbi Witmer, Carolyn Chu, Hong Jin, Wendy Richmond, Lucas Westling, Thomas Hollenbeck, Ashley Chong, Sally Franey, Todd Groessl, Michael Shapiro, Kathleen Effenberger, Konrad Arroyo, Angela Bretz, Ayako Honda, James Brown, Carina C. Sanchez, William P. Gordon, Jason Matzen, Nils Osterman, Simona Cotesta, Saskia M. Brachmann, Rainer Wilcken, Frederic Zecri, Kim S. Beyer, Valentina Molteni, Jacob R. Haling
DOI: 10.1021/acs.jmedchem.6c00127
Cited by: 1
References: 22

Abstract

Abstract The RAS Switch-II pockets’ discovery enabled targeting a challenging molecular site. Covalent KRASG12C inhibitors inspired efforts to find compounds for other KRAS mutations, notably KRASG12D and KRASG12V. A macrocyclization strategy led to the identification of an exceptionally potent lead compound 12. Highly optimized interactions in the pocket yielded strong affinity against KRASG12D and KRASG12V, potent inhibition of phospho-ERK in various KRAS mutant cell lines, and tumor regression in mouse xenograft models.

Fields of Study & Subjects

Protein Kinase Regulation and GTPase Signaling Receptor Mechanisms and Signaling Melanoma and MAPK Pathways

Publication details

Journal / source
Journal of Medicinal Chemistry
Publisher
American Chemical Society (ACS)
Volume
69
Issue
11
Pages
13165–13187
Publication date
19 May 2026
Language
EN