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ACS Infect Dis. 2016 Mar 11;2(3):180-186. Epub 2016 Jan 17.

Identification of "Preferred" Human Kinase Inhibitors for Sleeping Sickness Lead Discovery. Are Some Kinases Better than Others for Inhibitor Repurposing?

Author information

1
Department of Chemistry & Chemical Biology, Northeastern University , 360 Huntington Avenue, Boston, Massachusetts 02115, United States.
2
Computational Sciences Center of Emphasis, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02140, United States.
3
Tres Cantos Medicines Development Campus, DDW and CIB, GlaxoSmithKline , 28760 Tres Cantos, Spain.
4
Instituto de Parasitología y Biomedicina "López-Neyra", Consejo Superior de Investigaciones Científicas , 18100 Granada, Spain.
5
Department of Microbiology, Division of Parasitology, New York University School of Medicine , 341 East 25th Street New York, New York 10010, United States.
6
Experimental Therapeutics, Walter Reed Army Institute for Research , 2460 Linden Lane, Silver Spring, Maryland 20910, United States.
7
Department of Microbiology, Division of Parasitology, New York University School of Medicine, 341 East 25th Street New York, New York 10010, United States; Anti-Infectives Screening Core, New York University School of Medicine, New York, New York 10010, United States.

Abstract

A kinase-targeting cell-based high-throughput screen (HTS) against Trypanosoma brucei was recently reported, and this screening set included the Published Kinase Inhibitor Set (PKIS). From the PKIS was identified 53 compounds with pEC50 ≥ 6. Utilizing the published data available for the PKIS, a statistical analysis of these active antiparasitic compounds was performed, allowing identification of a set of human kinases having inhibitors that show a high likelihood for blocking T. brucei cellular proliferation in vitro. This observation was confirmed by testing other established inhibitors of these human kinases and by mining past screening campaigns at GlaxoSmithKline. Overall, although the parasite targets of action are not known, inhibitors of this set of human kinases displayed an enhanced hit rate relative to a random kinase-targeting HTS campaign, suggesting that repurposing efforts should focus primarily on inhibitors of these specific human kinases. We therefore term this statistical analysis-driven approach "preferred lead repurposing".

KEYWORDS:

Leishmania major; Plasmodium falciparum; Published Kinase Inhibitor Set; Trypanosoma brucei; Trypanosoma cruzi; preferred lead repurposing

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