Structure guided optimization of a fragment hit to imidazopyridine inhibitors of PI3K
ABSTRACT PI3 kinases are a family of lipid kinases mediating numerous cell processes such as proliferation, migration and differentiation. The PI3 Kinase pathway is often de-regulated in cancer through PI3Kα overexpression, gene amplification, mutations and PTEN phosphatase deletion. PI3K inhibitors represent therefore an attractive therapeutic modality for cancer treatment. Herein we describe how the potency of a benzothiazole fragment hit was quickly improved based on structural information and how this early chemotype was further optimized through scaffold hopping. This effort led to the identification of a series of 2-acetamido-5-heteroaryl imidazopyridines showing potent in vitro activity against all class I PI3Ks and attractive pharmacokinetic properties.
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ABSTRACT: Phosphoinositide 3-kinase γ (PI3Kγ) is an attractive target to potentially treat a range of disease states. Herein, we describe the evolution of a reported phenylthiazole pan-PI3K inhibitor into a family of potent and selective benzothiazole inhibitors. Using X-ray crystallography, we discovered that compound 22, occupies a previously unreported hydrophobic binding cleft adjacent to the ATP binding site of PI3Kγ and achieves its selectivity by exploiting natural sequence differences among PI3K isoforms in this region.Journal of Medicinal Chemistry 04/2014; 58(1). DOI:10.1021/jm500362j · 5.48 Impact Factor