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Publication Abstract from PubMed

Fibroblast growth factor receptors (FGFR) 2 and 3 have been established as drivers of numerous types of cancer with multiple drugs approved or entering late stage clinical trials. A limitation of current inhibitors is vulnerability to gatekeeper resistance mutations. Using a combination of targeted high-throughput screening and structure-based drug design, we have developed a series of aminopyrazole based FGFR inhibitors that covalently target a cysteine residue on the P-loop of the kinase. The inhibitors show excellent activity against the wild-type and gatekeeper mutant versions of the enzymes. Further optimization using SAR analysis and structure-based drug design led to analogues with improved potency and drug metabolism and pharmacokinetics properties.

Discovery of Aminopyrazole Derivatives as Potent Inhibitors of Wild-Type and Gatekeeper Mutant FGFR2 and 3.,Brawn RA, Cook A, Omoto K, Ke J, Karr C, Colombo F, Virrankoski M, Prajapati S, Reynolds D, Bolduc DM, Nguyen TV, Gee P, Borrelli D, Caleb B, Yao S, Irwin S, Larsen NA, Selvaraj A, Zhao X, Ioannidis S ACS Med Chem Lett. 2020 Dec 2;12(1):93-98. doi: 10.1021/acsmedchemlett.0c00517., eCollection 2021 Jan 14. PMID:33488969^[1]

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