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Clk and Dyrk1A Inhibitors as General Splicing Modulators and for the Potential Treatment of Down's Syndrome and Alzheimer's Dise

Posted Nov 22 2009 4:00pm

Description of Invention:
NIH investigators have discovered a series of potent, selective small molecule inhibitors of cdc2-like kinases (Clk) and dual-specificity tyrosine-regulated kinase 1A (Dyrk1A) with potential as modulators of gene splicing and within the treatment of Down's syndrome and Alzheimer's disease. Clk kinases are known to phosphorylate the prominent family of serine- and arginine-rich (SR) splicing proteins. Members of the Clk family have been implicated in the regulation of alternative splicing of PKCbetaII, TF, Tau and beta-globin pre-mRNA. Dyrk1A is a kinase that has been implicated in numerous aspects of neurological development and maintenance. The gene that encodes Dyrk1A is found on the Down's Syndrome-critical region on chromosome 21 and the over-expression of Dyrk1A is considered to be a primary contributor to the Down's syndrome phenotype. For instance, transgenic mice overexpressing Dyrk1A exhibit cognitive deficits, and blocking Dyrk1A in these transgenic animals has been shown to mitigate Down's-related deficits. Hyper-phosphorylation of Tau by Dyrk1A has also been directly implicated in the pathology and progression of Down's syndrome-associated Alzheimer's disease. Alzheimer's disease in general is also associated with pathological deposition of hyper-phosphorylated Tau. Thus, these molecules have the potential to treat both Down's syndrome and Alzheimer's disease.

  • Tools for the study of alternate gene splicing
  • Potential therapeutic for Down's syndrome
  • Potential therapeutic for Alzheimer's disease

Development Status:
Early stage

Craig J Thomas (NHGRI)

Patent Status:
HHS, Reference No. E-230-2009/0
US, Application No. 61/247,632 filed 01 Oct 2009

Relevant Publication:
  1. BT Mott et al. Evaluation of substituted 6-arylquinazolin-4-amines as potent and selective inhibitors of cdc2-like kinases (Clk). Bioorg Med Chem Lett. 2009 Dec 1;19(23):6700-6705. Epub ahead of print, 2009 Oct 3, doi:10.1016/j.bmcl.2009.09.121. [ PubMed abs ]

Licensing Status:
Available for licensing.

Collaborative Research Opportunity:
The NIH Chemical Genomics Center is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize appropriate lead compounds described in U.S. Provisional Application No. 61/247,632. Please contact Dr. Craig J. Thomas via e-mail ( ) for more information.

Central Nervous System
Central Nervous System - Therapeutics

For Additional Information Please Contact:
Steven Standley Ph.D.
NIH Office of Technology Transfer
6011 Executive Blvd. Suite 325,
Rockville, MD 20852
United States
Phone: 301-435-4074
Fax: 301-402-0220

Ref No: 2040

Updated: 11/2009

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