9u7s
FGFR2 kinase domain with a macrocyclic compound 8r
Structural highlights
Publication Abstract from PubMedAlterations in the FGFR family act as oncogenic drivers for multiple pediatric and adult tumors, leading to the development and approval of several FGFR inhibitors. However, the on-target gatekeeper and "molecular brake" mutations confer clinically acquired resistance to the FDA-approved FGFR inhibitors, which presents a significant unmet medical need. Herein, we report the first novel macrocycle-based FGFR inhibitors targeting both wild-type and clinically acquired variants of the FGFR family. The representative compound 8r potently inhibited FGFR1/2/3 with IC(50) values of 10.0, 6.9, and 30.2 nM, respectively. Compound 8r also potently suppressed proliferation of a series of FGFR-driven cancer cell lines with IC(50) values of 2.0-13.3 nM. Compared with futibatinib, 8r exhibited superior inhibitory activity toward FGFR1(V561M), FGFR2(V564F), and FGFR2(N549K) mutations with IC(50) values of 6.8, 0.7, and 0.8 nM, respectively. Moreover, 8r demonstrated favorable antitumor efficacy in an RT112/84 bladder cancer xenograft model. This work provides a promising macrocycle-based lead compound for the treatment of FGFR-driven cancers. Design, Synthesis, and Biological Evaluation of the First Novel Macrocycle-Based FGFR Inhibitors That Overcome Clinically Acquired Resistance.,Xiang S, Chen X, Lin J, Lin X, Lin Q, Song X, Yan L, Peng H, Tu Z, Patterson AV, Smaill JB, Tu Y, Chen Y, Lu X J Med Chem. 2026 Jan 22;69(2):1178-1198. doi: 10.1021/acs.jmedchem.5c02462. Epub , 2026 Jan 5. PMID:41490805[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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