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

详细信息    查看全文

• 作者：Emanuele Amata ; Hualin Xi ; Gonzalo Colmenarejo ; Rosario Gonzalez-Diaz ; Carlos Cordon-Obras ; Manuela Berlanga ; Pilar Manzano ; Jessey Erath ; Norma E. Roncal ; Patricia J. Lee ; Susan E. Leed ; Ana Rodriguez ; Richard J. Sciotti ; Miguel Navarro ; Michael P. Pollastri
• 刊名：ACS Infectious Diseases
• 出版年：2016
• 出版时间：March 11, 2016
• 年：2016
• 卷：2
• 期：3
• 页码：180-186
• 全文大小：380K
• ISSN：2373-8227

文摘

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”.