Human CDC2-Like Kinase 1 (CLK1): A Novel Target for Alzheimer’s Disease
Ravindra Mishra
, Piyush Pankaj , Darakhshan Gazala Bari , Dr.Saurabh Sharma
Cdc2 like kinase (CLK), Alzheimer, SR proteins, protein kinases, CLK1 inhibitors.
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 typi- cal protein kinase fold. CLK1 has been shown to autophosphorylate on serine, threonine and tyrosine residues and phos- phorylate 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 in- volved 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 splic- ing 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 that the marine sponge metabolite hymeniald- isine and a dichloroindolyl enamino nitrile (KH-CB19) have binding interaction 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 dis- ease drug discovery and development. In addition, the recent developments in drug discovery efforts targeting human CDC2-like kinase 1 are also highlighted.
"Human CDC2-Like Kinase 1 (CLK1): A Novel Target for Alzheimer’s Disease", IJSDR - International Journal of Scientific Development and Research (www.IJSDR.org), ISSN:2455-2631, Vol.4, Issue 12, page no.232 - 240, December-2019, Available :https://ijsdr.org/papers/IJSDR1912046.pdf
Volume 4
Issue 12,
December-2019
Pages : 232 - 240
Paper Reg. ID: IJSDR_191993
Published Paper Id: IJSDR1912046
Downloads: 000347416
Research Area: Engineering
Country: -, -, --
ISSN: 2455-2631 | IMPACT FACTOR: 9.15 Calculated By Google Scholar | ESTD YEAR: 2016
An International Scholarly Open Access Journal, Peer-Reviewed, Refereed Journal Impact Factor 9.15 Calculate by Google Scholar and Semantic Scholar | AI-Powered Research Tool, Multidisciplinary, Monthly, Multilanguage Journal Indexing in All Major Database & Metadata, Citation Generator
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