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Phosphoinositide-dependent protein kinase-1(PDK1) is a master regulator of the AGC family of kinases and an integral component of the PI3K/AKT/mTOR pathway. As this pathway is among the most commonly deregulated across all cancers, a selective inhibitor of PDK1 might have utility as an anticancer agent. Herein we describe our lead optimization of compound 1 toward highly potent and selective PDK1 inhibitors via a structure-based design strategy. The most potent and selective inhibitors demonstrated submicromolar activity as measured by inhibition of phosphorylation of PDK1 substrates as well as antiproliferative activity against a subset of AML cell lines. In addition, reduction of phosphorylation of PDK1 substrates was demonstrated in vivo in mice bearing OCl-AML2 xenografts. These observations demonstrate the utility of these molecules as tools to further delineate the biology of PDK1 and the potential pharmacological uses of a PDK1 inhibitor.

Fragment screening of phosphoinositide-dependent kinase-1 (PDK1) in a biochemical kinase assay afforded hits that were characterized and prioritized based on ligand efficiency and binding interactions with PDK1 as determined by NMR. Subsequent crystallography and follow-up screening led to the discovery of aminoindazole 19, a potent leadlike PDK1 inhibitor with high ligand efficiency. Well-defined structure−activity relationships and protein crystallography provide a basis for further elaboration and optimization of 19 as a PDK1 inhibitor.