Discovery and Characterization of a Chemical Probe for Cyclin-Dependent Kinase-Like 2.

Autor:	Bashore FM; Structural Genomics Consortium (SGC), UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Min SM; Structural Genomics Consortium (SGC), UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Chen X; Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, U.K., Howell S; Structural Genomics Consortium (SGC), UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Rinderle CH; Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, Texas 76107, United States., Morel G; Kinases and Brain Development Laboratory, The Francis Crick Institute, London NW1 1AT, U.K., Silvaroli JA; Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, United States., Wells CI; Structural Genomics Consortium (SGC), UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Bunnell BA; Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, Texas 76107, United States., Drewry DH; Structural Genomics Consortium (SGC), UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.; UNC Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Pabla NS; Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, United States., Ultanir SK; Kinases and Brain Development Laboratory, The Francis Crick Institute, London NW1 1AT, U.K., Bullock AN; Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, U.K., Axtman AD; Structural Genomics Consortium (SGC), UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2024 Jul 03; Vol. 15 (8), pp. 1325-1333. Date of Electronic Publication: 2024 Jul 03 (Print Publication: 2024).
DOI:	10.1021/acsmedchemlett.4c00219
Abstrakt:	Acylaminoindazole-based inhibitors of CDKL2 were identified via analyses of cell-free binding and selectivity data. Compound 9 was selected as a CDKL2 chemical probe based on its potent inhibition of CDKL2 enzymatic activity, engagement of CDKL2 in cells, and excellent kinome-wide selectivity, especially when used in cells. Compound 16 was designed as a negative control to be used alongside compound 9 in experiments to interrogate CDKL2-mediated biology. A solved cocrystal structure of compound 9 bound to CDKL2 highlighted key interactions it makes within its ATP-binding site. Inhibition of downstream phosphorylation of EB2, a CDKL2 substrate, in rat primary neurons provided evidence that engagement of CDKL2 by compound 9 in cells resulted in inhibition of its activity. When used at relevant concentrations, compound 9 does not impact the viability of rat primary neurons or certain breast cancer cells nor elicit consistent changes in the expression of proteins involved in epithelial-mesenchymal transition. Competing Interests: The authors declare no competing financial interest. (© 2024 The Authors. Published by American Chemical Society.)
Databáze:	MEDLINE
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