8CIE

Crystal structure of the human CDKL5 kinase domain with compound YL-354

Summary for 8CIE

• Entry DOI: 10.2210/pdb8cie/pdb
• Descriptor: Cyclin-dependent kinase-like 5, 4-[[3,5-bis(fluoranyl)phenyl]carbonylamino]-~{N}-piperidin-4-yl-1~{H}-pyrazole-3-carboxamide, SULFATE ION, ... (4 entities in total)
• Functional Keywords: kinase, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 35677.11

Authors

Richardson, W.,Chen, X.,Newman, J.A.,Bakshi, S.,Lakshminarayana, B.,Brooke, L.,Bullock, A.N. (deposition date: 2023-02-09, release date: 2023-06-14, Last modification date: 2024-03-27)

Primary citation

Ong, H.W.,Liang, Y.,Richardson, W.,Lowry, E.R.,Wells, C.I.,Chen, X.,Silvestre, M.,Dempster, K.,Silvaroli, J.A.,Smith, J.L.,Wichterle, H.,Pabla, N.S.,Ultanir, S.K.,Bullock, A.N.,Drewry, D.H.,Axtman, A.D.
Discovery of a Potent and Selective CDKL5/GSK3 Chemical Probe That Is Neuroprotective.
Acs Chem Neurosci, 14:1672-1685, 2023

PubMed 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 compound that has advanced to phase II clinical trials and is a known inhibitor of several cyclin-dependent kinases (CDKs) and cyclin-dependent kinase-like kinases (CDKLs). We identified analog 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 demonstrates excellent selectivity and only retains GSK3α/β affinity. We next demonstrated the inhibition of downstream CDKL5 and GSK3α/β signaling and solved a co-crystal structure of analog bound to human CDKL5. A structurally similar analog () proved to lack CDKL5 affinity and maintain potent and selective inhibition of GSK3α/β, making it a suitable negative control. Finally, we used our chemical probe pair ( and ) to demonstrate that inhibition of CDKL5 and/or GSK3α/β promotes the survival of human motor neurons exposed to endoplasmic reticulum 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.

PubMed: 37084253
DOI: 10.1021/acschemneuro.3c00135

Experimental method

X-RAY DIFFRACTION (2.2 Å)