Authors
Dean P Phillips, Phil B Alper, Dmitry Borkin, Dong Han, Sarah E Kochanek, Jitendra Gurjar, Casey J N Mathison, John M Nelson, Wei Pei, Bao Ngoc Nguyen, Timothy Hoffman, Barun Okram, Truc N Nguyen, Songchun Jiang, Brian T Masick, Zhicheng Wang, Charles Y Cho, Hong Yin, Yu Chen, Jose Juarez, Yong Jia, Vicki Zhou, Guoxun Liu, Clifford Wright, Trish Nguyen, Deborah A Knee, Qian Liu, Jun Liu, Jie Li, Cyrus Virata, Cesar de Oliveira, Michael DiDonato, Badry Bursulaya, Agnes Vidal-Biggart, David H Jones, Darbi Witmer, Carolyn Chu, Hong Jin, Ananda Herath, Wendy Richmond, Todd Groessl, Michael Shapiro, Kathleen Effenberger, Konrad Arroyo, Angela Bretz, Ayako Honda, William P Gordon, Valentina Molteni, Jacob R Haling
Published in
Journal of medicinal chemistry. Volume 69. Issue 17. Pages 20698-20718. Sep 10, 2026.
Abstract
Starting from our internally discovered, potent panKRAS inhibitor BRSD-143 (1), we executed a targeted bioisosteric optimization of the naphthol and fluoropyrrolizidine motifs to preserve (or increase) KRAS pan-inhibitory potency while improving DMPK/ADME liabilities. These studies delivered 12 (BRSD-212), a highly potent and efficacious lead in which (2-azabicyclo[4.2.0]octan-6-yl)methanol (ABO) serves as a bioisostere for the widely deployed 2-fluoropyrrolizidine substituent. In parallel, replacement of the naphthol moiety with an indazole afforded 21, which demonstrated improved pharmacokinetic performance and ADME characteristics by mitigating glucuronidation-mediated clearance as the dominant metabolic pathway.
PMID:
42720494
Bibliographic data and abstract were imported from PubMed on 10 Sep 2026.
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