Download MendeleyStructure-Based Design of Potent and Selective 3-Phosphoinositide-Dependent Kinase-1 (PDK1) Inhibitors.
Medina, J.R., Becker, C.J., Blackledge, C.W., Duquenne, C., Feng, Y., Grant, S.W., Heerding, D., Li, W.H., Miller, W.H., Romeril, S.P., Scherzer, D., Shu, A., Bobko, M.A., Chadderton, A.R., Dumble, M., Gardiner, C.M., Gilbert, S., Liu, Q., Rabindran, S.K., Sudakin, V., Xiang, H., Brady, P.G., Campobasso, N., Ward, P., Axten, J.M.(2011) J Med Chem 54: 1871-1895
- PubMed: 21341675
- DOI: https://doi.org/10.1021/jm101527u
- Primary Citation of Related Structures:
3QCQ, 3QCS, 3QCX, 3QCY, 3QD0, 3QD3, 3QD4 - PubMed Abstract:
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.
Organizational Affiliation:
Oncology Research, GlaxoSmithKline, Collegeville, Pennsylvania 19426, United States. [email protected]
