Artem Shvartsbart, Jeremy J Roach, Michael R Witten, Holly Koblish, Jennifer J Harris, Maryanne Covington, Rodrigo Hess, Luping Lin, Michelle Frascella, Lisa Truong, Lynn Leffet, Patricia Conlen, Elham Beshad, Ron Klabe, Kamna Katiyar, Laura Kaldon, Ruth Young-Sciame, Xin He, Susan Petusky, Kwang-Jong Chen, April Horsey, Hsiang-Ting Lei, Leslie B Epling, Marc C Deller, Oleg Vechorkin, Wenqing Yao
Upregulation of the fibroblast growth factor receptor (FGFR) signaling pathway has been implicated in multiple cancer types, including cholangiocarcinoma and bladder cancer. Consequently, small molecule inhibition of FGFR has emerged as a promising therapy for patients suffering from these diseases. First-generation pan-FGFR inhibitors, while highly effective, suffer from several drawbacks. These include treatment-related hyperphosphatemia and significant loss of potency for the mutant kinases. Herein, we present the discovery and optimization of novel FGFR2/3 inhibitors that largely maintain potency for the common gatekeeper mutants and have excellent selectivity over FGFR1...
November 10, 2022: Journal of Medicinal Chemistry