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

Autor:	Brawn RA; H3 Biomedicine, 300 Technology Square, Cambridge, Massachusetts 02139, United States., Cook A; H3 Biomedicine, 300 Technology Square, Cambridge, Massachusetts 02139, United States., Omoto K; H3 Biomedicine, 300 Technology Square, Cambridge, Massachusetts 02139, United States., Ke J; H3 Biomedicine, 300 Technology Square, Cambridge, Massachusetts 02139, United States., Karr C; H3 Biomedicine, 300 Technology Square, Cambridge, Massachusetts 02139, United States., Colombo F; H3 Biomedicine, 300 Technology Square, Cambridge, Massachusetts 02139, United States., Virrankoski M; H3 Biomedicine, 300 Technology Square, Cambridge, Massachusetts 02139, United States., Prajapati S; H3 Biomedicine, 300 Technology Square, Cambridge, Massachusetts 02139, United States., Reynolds D; H3 Biomedicine, 300 Technology Square, Cambridge, Massachusetts 02139, United States., Bolduc DM; H3 Biomedicine, 300 Technology Square, Cambridge, Massachusetts 02139, United States., Nguyen TV; H3 Biomedicine, 300 Technology Square, Cambridge, Massachusetts 02139, United States., Gee P; H3 Biomedicine, 300 Technology Square, Cambridge, Massachusetts 02139, United States., Borrelli D; H3 Biomedicine, 300 Technology Square, Cambridge, Massachusetts 02139, United States., Caleb B; H3 Biomedicine, 300 Technology Square, Cambridge, Massachusetts 02139, United States., Yao S; H3 Biomedicine, 300 Technology Square, Cambridge, Massachusetts 02139, United States., Irwin S; H3 Biomedicine, 300 Technology Square, Cambridge, Massachusetts 02139, United States., Larsen NA; H3 Biomedicine, 300 Technology Square, Cambridge, Massachusetts 02139, United States., Selvaraj A; H3 Biomedicine, 300 Technology Square, Cambridge, Massachusetts 02139, United States., Zhao X; H3 Biomedicine, 300 Technology Square, Cambridge, Massachusetts 02139, United States., Ioannidis S; H3 Biomedicine, 300 Technology Square, Cambridge, Massachusetts 02139, United States.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2020 Dec 02; Vol. 12 (1), pp. 93-98. Date of Electronic Publication: 2020 Dec 02 (Print Publication: 2021).
DOI:	10.1021/acsmedchemlett.0c00517
Abstrakt:	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. Competing Interests: The authors declare no competing financial interest. (© 2020 American Chemical Society.)
Databáze:	MEDLINE
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