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Publication Abstract from PubMed

Fibroblast growth factor receptor 3 (FGFR3) is an attractive therapeutic target for the treatment of patients with bladder cancer harboring genetic alterations in FGFR3. We identified pyrimidine derivative 20b, which induced tumor regression following oral administration to a bladder cancer xenograft mouse model. Compound 20b was discovered by optimizing lead compound 1, which we reported previously. Specifically, reducing the molecular size of the substituent at the 4-position and replacing the linker of the 5-position in the pyrimidine scaffold resulted in an increase in systemic exposure. Furthermore, introduction of two fluorine atoms into the 3,5-dimethoxyphenyl ring enhanced FGFR3 inhibitory activity. Molecular dynamics (MD) simulation of 20b suggested that the fluorine atom interacts with the main chain NH moiety of Asp635 via a hydrogen bond.

Synthesis and structure-activity relationships of pyrimidine derivatives as potent and orally active FGFR3 inhibitors with both increased systemic exposure and enhanced in vitro potency.,Kuriwaki I, Kameda M, Iikubo K, Hisamichi H, Kawamoto Y, Kikuchi S, Moritomo H, Kondoh Y, Terasaka T, Amano Y, Tateishi Y, Echizen Y, Iwai Y, Noda A, Tomiyama H, Nakazawa T, Hirano M Bioorg Med Chem. 2021 Jan 16;33:116019. doi: 10.1016/j.bmc.2021.116019. PMID:33486159^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.