Design of selective PI3Kα inhibitors starting from a promiscuous pan kinase scaffold

• Published in: Bioorganic & medicinal chemistry letters 2015-07, Vol.25 (13), p.2679-2685
• Main Authors: Barlaam, Bernard, Cosulich, Sabina, Fitzek, Martina, Green, Stephen, Harris, Craig S., Hudson, Kevin, Lambert-van der Brempt, Christine, Ouvry, Gilles, Page, Ken, Ruston, Linette, Ward, Lara, Delouvrié, Bénédicte
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Binding Sites; Biomarkers, Tumor - antagonists & inhibitors; Biomarkers, Tumor - chemistry; Biomarkers, Tumor - genetics; Cell Line, Tumor; Class I Phosphatidylinositol 3-Kinases; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Kinase selectivity; Models, Molecular; Mutant Proteins - antagonists & inhibitors; Mutant Proteins - chemistry; Mutant Proteins - genetics; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - chemistry; Phosphatidylinositol 3-Kinases - genetics; PI3Kα inhibitor; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Structure-Activity Relationship; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - pharmacology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2015.04.084

[Display omitted] Starting from compound 1, a potent PI3Kα inhibitor having poor general kinase selectivity, we used structural data and modelling to identify key exploitable differences between PI3Kα and the other kinases. This approach led us to design chemical modifications of the central pyrazole, which solved the poor kinase selectivity seen as a strong liability for the initial compound 1. Amongst the modifications explored, a 1,3,4-triazole ring (as in compound 4) as a replacement of the initial pyrazole provided good potency against PI3Kα, with excellent kinase selectivity.