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

  • J Med Chem. 2026 Jun 11;69(11):13165-13187. doi: 10.1021/acs.jmedchem.6c00127.
Dean P Phillips  1 Phil B Alper  1 Charles Y Cho  1 Dmitry Borkin  1 Dong Han  1 Sarah E Kochanek  2 Agnes Vidal-Biggart  1 Ananda Herath  1 Jitendra Gurjar  1 Wenshuo Lu  1 Casey J N Mathison  1 John M Nelson  1 Wei Pei  1 Shanshan Yan  1 Bao Ngoc Nguyen  1 Timothy Hoffman  1 Barun Okram  1 Truc N Nguyen  1 Songchun Jiang  1 Brian T Masick  1 Zhicheng Wang  1 Victor Nikulin  1 Hong Yin  1 Yu Chen  1 Jose Juarez  1 Yelena Sarkisova  1 Yong Jia  1 Vicki Zhou  1 Guoxun Liu  1 Xianzhong Liu  1 Min Lu  1 Brandon L Taylor  1 Lang Huynh  1 Yu Wang  1 Reynand Pacoma  1 Janine Baaten  1 Kathryn Topolewski  1 Clifford Wright  1 Trish Nguyen  1 Deborah A Knee  1 Qian Liu  1 Jun Liu  1 Jie Li  1 Cyrus Virata  1 Sergio Briones  1 Michael DiDonato  1 Badry Bursulaya  1 David H Jones  1 Darbi Witmer  1 Carolyn Chu  1 Hong Jin  1 Wendy Richmond  1 Lucas Westling  1 Thomas Hollenbeck  1 Ashley Chong  1 Sally Franey  1 Todd Groessl  1 Michael Shapiro  1 Kathleen Effenberger  1 Konrad Arroyo  1 Angela Bretz  1 Ayako Honda  2 James Brown  2 Carina C Sanchez  2 William P Gordon  1 Jason T Matzen  1 Nils Osterman  3 Simona Cotesta  3 Saskia M Brachmann  3 Rainer Wilcken  3 Frederic Zecri  2 Kim S Beyer  1 Valentina Molteni  1 Jacob R Haling  1
Affiliations
  • 1. Novartis Biomedical Research, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
  • 2. Novartis Biomedical Research, Cambridge, Massachusetts 02139, United States.
  • 3. Novartis Biomedical Research, Basel CH-4056, Switzerland.
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.

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