Article
Targeting Multiple KRAS Mutations with High-Affinity Macrocyclic Inhibitors: From Discovery to Preclinical Validation.
Journal of medicinal chemistry - 11 Jun 2026
Phillips Dean P, Alper Phil B, Cho Charles Y, Borkin Dmitry, Han Dong, Kochanek Sarah E, Vidal-Biggart Agnes, Herath Ananda, Gurjar Jitendra, Lu Wenshuo, Mathison Casey J N, Nelson John M, Pei Wei, Yan Shanshan, Nguyen Bao Ngoc, Hoffman Timothy, Okram Barun, Nguyen Truc N, Jiang Songchun, Masick Brian T, Wang Zhicheng, Nikulin Victor, Yin Hong, Chen Yu, Juarez Jose, Sarkisova Yelena, Jia Yong, Zhou Vicki, Liu Guoxun, Liu Xianzhong, Lu Min, Taylor Brandon L, Huynh Lang, Wang Yu, Pacoma Reynand, Baaten Janine, Topolewski Kathryn, Wright Clifford, Nguyen Trish, Knee Deborah A, Liu Qian, Liu Jun, Li Jie, Virata Cyrus, Briones Sergio, DiDonato Michael, Bursulaya Badry, Jones David H, Witmer Darbi, Chu Carolyn, Jin Hong, Richmond Wendy, Westling Lucas, Hollenbeck Thomas, Chong Ashley, Franey Sally, Groessl Todd, Shapiro Michael, Effenberger Kathleen, Arroyo Konrad, Bretz Angela, Honda Ayako, Brown James, Sanchez Carina C, Gordon William P, Matzen Jason T, Osterman Nils, Cotesta Simona, Brachmann Saskia M, Wilcken Rainer, Zecri Frederic, Beyer Kim S, Molteni Valentina, Haling Jacob R
Abstract excerpt
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...
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