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

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

  • bioRxiv. 2024 May 14:2024.05.12.593776. doi: 10.1101/2024.05.12.593776.
Frances M Bashore 1,  Sophia M Min 1,  Xiangrong Chen 2,  Stefanie Howell 1,  Caroline H Rinderle 3,  Gabriel Morel 4,  Josie A Silvaroli 5,  Carrow I Wells 1,  Bruce A Bunnell 3,  David H Drewry 1 6,  Navjot S Pabla 5,  Sila K Ultanir 4,  Alex N Bullock 2,  Alison D Axtman 1
Affiliations

Affiliations

  • 1 Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 2 Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK.
  • 3 Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
  • 4 Kinases and Brain Development Laboratory, The Francis Crick Institute, London, NW1 1AT, UK.
  • 5 Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, 43210, United States of America.
  • 6 UNC Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
PMID: 38798634 DOI: 10.1101/2024.05.12.593776
Abstract

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 co-crystal 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.

Keywords

CDKL2; acylaminoindazole; chemical probe; cyclin dependent kinase-like 2; epithelial–mesenchymal transition; protein kinase.

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