title: Identification of "Preferred" Human Kinase Inhibitors for Sleeping Sickness Lead Discovery. Are Some Kinases Better than Others for Inhibitor Repurposing?
abstract: A kinase-targeting cell-based high-throughput screen (HTS) againstTrypanosoma bruceiwas 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 blockingT. bruceicellular 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".
authors.affiliation: Department of Chemistry & Chemical Biology, Northeastern University , 360 Huntington Avenue, Boston, Massachusetts 02115, United States.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Amata
authors.affiliation: Computational Sciences Center of Emphasis, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02140, United States.
authors.forename: Hualin
authors.initials: H
authors.lastname: Xi
authors.affiliation: Tres Cantos Medicines Development Campus, DDW and CIB, GlaxoSmithKline , 28760 Tres Cantos, Spain.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Colmenarejo
authors.affiliation: Instituto de Parasitología y Biomedicina "López-Neyra", Consejo Superior de Investigaciones Científicas , 18100 Granada, Spain.
authors.forename: Rosario
authors.initials: R
authors.lastname: Gonzalez-Diaz
authors.affiliation: Instituto de Parasitología y Biomedicina "López-Neyra", Consejo Superior de Investigaciones Científicas , 18100 Granada, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordon-Obras
authors.affiliation: Tres Cantos Medicines Development Campus, DDW and CIB, GlaxoSmithKline , 28760 Tres Cantos, Spain.
authors.forename: Manuela
authors.initials: M
authors.lastname: Berlanga
authors.affiliation: Tres Cantos Medicines Development Campus, DDW and CIB, GlaxoSmithKline , 28760 Tres Cantos, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Manzano
authors.affiliation: Department of Microbiology, Division of Parasitology, New York University School of Medicine , 341 East 25th Street New York, New York 10010, United States.
authors.forename: Jessey
authors.initials: J
authors.lastname: Erath
authors.affiliation: Experimental Therapeutics, Walter Reed Army Institute for Research , 2460 Linden Lane, Silver Spring, Maryland 20910, United States.
authors.forename: Norma E
authors.initials: NE
authors.lastname: Roncal
authors.affiliation: Experimental Therapeutics, Walter Reed Army Institute for Research , 2460 Linden Lane, Silver Spring, Maryland 20910, United States.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Lee
authors.affiliation: Experimental Therapeutics, Walter Reed Army Institute for Research , 2460 Linden Lane, Silver Spring, Maryland 20910, United States.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Leed
authors.affiliation: 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.
authors.forename: Ana
authors.initials: A
authors.lastname: Rodriguez
authors.affiliation: Experimental Therapeutics, Walter Reed Army Institute for Research , 2460 Linden Lane, Silver Spring, Maryland 20910, United States.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Sciotti
authors.affiliation: Instituto de Parasitología y Biomedicina "López-Neyra", Consejo Superior de Investigaciones Científicas , 18100 Granada, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Navarro
authors.affiliation: Department of Chemistry & Chemical Biology, Northeastern University , 360 Huntington Avenue, Boston, Massachusetts 02115, United States.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Pollastri
keywords: Leishmania major; Plasmodium falciparum; Published Kinase Inhibitor Set; Trypanosoma brucei; Trypanosoma cruzi; preferred lead repurposing