Dataset Information

Discovery of Aminopyrazole Derivatives as Potent Inhibitors of Wild-Type and Gatekeeper Mutant FGFR2 and 3.

ABSTRACT: 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.

SUBMITTER: Brawn RA

PROVIDER: S-EPMC7812672 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Discovery of Aminopyrazole Derivatives as Potent Inhibitors of Wild-Type and Gatekeeper Mutant FGFR2 and 3.

Brawn Ryan A RA Cook Andrew A Omoto Kiyoyuki K Ke Jiyuan J Karr Craig C Colombo Federico F Virrankoski Milena M Prajapati Sudeep S Reynolds Dominic D Bolduc David M DM Nguyen Tuong-Vi TV Gee Patricia P Borrelli Deanna D Caleb Benjamin B Yao Shihua S Irwin Sean S Larsen Nicholas A NA Selvaraj Anand A Zhao Xuesong X Ioannidis Stephanos S

ACS medicinal chemistry letters 20201202 1

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 ...[more]

PMID: 33488969

Dataset Information

Discovery of Aminopyrazole Derivatives as Potent Inhibitors of Wild-Type and Gatekeeper Mutant FGFR2 and 3.

Publications

Discovery of Aminopyrazole Derivatives as Potent Inhibitors of Wild-Type and Gatekeeper Mutant FGFR2 and 3.

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