8S6I

Crystal structure of the human CDKL2 kinase domain with Compound 9

This is a non-PDB format compatible entry.

Summary for 8S6I

• Entry DOI: 10.2210/pdb8s6i/pdb
• Descriptor: Cyclin-dependent kinase-like 2, ~{N}-[6-[3-[(2-methylpropylsulfonylamino)methyl]phenyl]-1~{H}-indazol-3-yl]cyclopropanecarboxamide, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: kinase, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 39038.65

Authors

Chen, X.,Ni, X.,Brooke, L.,Bullock, A.N. (deposition date: 2024-02-27, release date: 2025-02-26)

Primary citation

Bashore, F.M.,Min, S.M.,Chen, X.,Howell, S.,Rinderle, C.H.,Morel, G.,Silvaroli, J.A.,Wells, C.I.,Bunnell, B.A.,Drewry, D.H.,Pabla, N.S.,Ultanir, S.K.,Bullock, A.N.,Axtman, A.D.
Discovery and Characterization of a Chemical Probe for Cyclin-Dependent Kinase-Like 2.
Acs Med.Chem.Lett., 15:1325-1333, 2024

PubMed Abstract: Acylaminoindazole-based inhibitors of CDKL2 were identified via analyses of cell-free binding and selectivity data. Compound 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 was designed as a negative control to be used alongside compound in experiments to interrogate CDKL2-mediated biology. A solved cocrystal structure of compound 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 in cells resulted in inhibition of its activity. When used at relevant concentrations, compound 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.

PubMed: 39140040
DOI: 10.1021/acsmedchemlett.4c00219

Experimental method

X-RAY DIFFRACTION (1.72 Å)