2. Academic Validation
  3. A Potent and Selective CDKL5/GSK3 Chemical Probe is Neuroprotective

A Potent and Selective CDKL5/GSK3 Chemical Probe is Neuroprotective

  • bioRxiv. 2023 Feb 10:2023.02.09.527935. doi: 10.1101/2023.02.09.527935.
Han Wee Ong 1,  Yi Liang 1,  William Richardson 2,  Emily R Lowry 3,  Carrow I Wells 1,  Xiangrong Chen 2,  Margaux Silvestre 4,  Kelvin Dempster 4,  Josie A Silvaroli 5,  Jeffery L Smith 1,  Hynek Wichterle 6,  Navjot S Pabla 5,  Sila K Ultanir 4,  Alex N Bullock 2,  David H Drewry 7,  Alison D Axtman 1
Affiliations

Affiliations

  • 1 Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, United States of America.
  • 2 Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7DQ, United Kingdom.
  • 3 Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York, 10032, United States of America; The Project ALS Therapeutics Core, Columbia University Irving Medical Center, New York, New York, 10032, United States of America.
  • 4 Kinases and Brain Development Laboratory, The Francis Crick Institute, London, NW1 1AT, United Kingdom.
  • 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 Departments of Pathology and Cell Biology, Neurology, Neuroscience, Rehabilitation and Regenerative Medicine, Columbia University Irving Medical Center, New York, New York, 10032, United States of America; Center for Motor Neuron Biology and Disease, Columbia University Irving Medical Center, New York, New York, 10032, United States of America; Columbia Stem Cell Initiative, Columbia University Irving Medical Center, New York, New York, 10032, United States of America; The Project ALS Therapeutics Core, Columbia University Irving Medical Center, New York, New York, 10032, United States of America.
  • 7 Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, United States of America; UNC Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, United States of America.
PMID: 36798313 DOI: 10.1101/2023.02.09.527935
Abstract

Despite mediating several essential processes in the brain, including during development, cyclin-dependent kinase-like 5 (CDKL5) remains a poorly characterized human protein kinase. Accordingly, its substrates, functions, and regulatory mechanisms have not been fully described. We realized that availability of a potent and selective small molecule probe targeting CDKL5 could enable illumination of its roles in normal development as well as in diseases where it has become aberrant due to mutation. We prepared analogs of AT-7519, a known inhibitor of several cyclin dependent and cyclin-dependent kinase-like kinases that has been advanced into Phase II clinical trials. We identified analog 2 as a highly potent and cell-active chemical probe for CDKL5/GSK3 (glycogen synthase kinase 3). Evaluation of its kinome-wide selectivity confirmed that analog 2 demonstrates excellent selectivity and only retains GSK3α/β affinity. As confirmation that our chemical probe is a high-quality tool to use in directed biological studies, we demonstrated inhibition of downstream CDKL5 and GSK3α/β signaling and solved a co-crystal structure of analog 2 bound to CDKL5. A structurally similar analog ( 4 ) proved to lack CDKL5 affinity and maintain potent and selective inhibition of GSK3α/β. Finally, we used our chemical probe pair ( 2 and 4 ) to demonstrate that inhibition of CDKL5 and/or GSK3α/β promotes the survival of human motor neurons exposed to endoplasmic reticulum (ER) stress. We have demonstrated a neuroprotective phenotype elicited by our chemical probe pair and exemplified the utility of our compounds to characterize the role of CDKL5/GSK3 in neurons and beyond.

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