Title:Human CDC2-Like Kinase 1 (CLK1): A Novel Target for Alzheimer’s Disease
Volume: 15
Issue: 5
Author(s): Princi Jain, Chandrabose Karthikeyan, N.S. Hari Narayana Moorthy, Digambar Kumar Waiker, Arvind Kumar Jain and Piyush Trivedi
Affiliation:
Keywords:
Cdc2 like kinase (CLK), Alzheimer’s disease, SR proteins, protein kinases, CLK1 inhibitors.
Abstract: The cdc2-like kinases (CLKs) are an evolutionarily conserved group of dual specificity kinases belonging to
the CMGC (cyclin-dependent kinases (CDKs), mitogen-activated protein kinases (MAP kinases), glycogen synthase
kinases (GSK) and CDK-like kinases). The CLK family consists of four isoforms namely CLK1, CLK2, CLK3 and
CLK4. The human CLK1 encoded protein comprises 454 amino acids and the catalytic domain of CLK1 exhibits the typical
protein kinase fold. CLK1 has been shown to autophosphorylate on serine, threonine and tyrosine residues and phosphorylate
exogenous substrates on serine and threonine residues. CLK1 plays an important role in the regulation of RNA
splicing through phosphorylation of members of the serine and arginine-rich (SR) family of splicing factors. CLK1 is involved
in the pathophysiology of Alzheimer’s disease by phosphorylating the serine residue in SR proteins. Nuclear
speckles of the nucleoplasm contain the stored form of SR proteins and are moderately responsible for the choice of splicing
sites during pre-mRNA splicing. Hence, the inhibition of CLK1 can be used as a therapeutic strategy for Alzheimer’s
disease. Many natural and synthetic molecules are reported to possess CLK1 inhibitory activity. Some specific examples
are Marine alkaloid Leucettamine B and KH-CB19. Leucettamine B is a potent inhibitor of CLK1 (15 nM), Dyrk1A (40
nM), and Dyrk2 (35 nM) and a moderate inhibitor of CLK3 (4.5 µM) whereas KH-CB19 is a highly specific and potent
inhibitor of the CLK1/CLK4. X-ray crystallographic studies have revealed the binding mode of marine sponge metabolite
hymenialdisine and a dichloroindolyl enamino nitrile (KH-CB19) to CLK1. This review focuses on the role of CLKs in
the pathophysiology of Alzheimer's disease and therapeutic potential of targeting CLK1 in Alzheimer's disease drug discovery
and development. In addition, the recent developments in drug discovery efforts targeting human CLK1 are also
highlighted.
