Structure-based design of potent and selective 3-phosphoinositide-dependent kinase-1 (PDK1) inhibitors

  • J Med Chem. 2011 Mar 24;54(6):1871-95. doi: 10.1021/jm101527u.
Jesús R Medina  1 ,  Christopher J Becker ,  Charles W Blackledge ,  Celine Duquenne ,  Yanhong Feng ,  Seth W Grant ,  Dirk Heerding ,  William H Li ,  William H Miller ,  Stuart P Romeril ,  Daryl Scherzer ,  Arthur Shu ,  Mark A Bobko ,  Antony R Chadderton ,  Melissa Dumble ,  Christine M Gardiner ,  Seth Gilbert ,  Qi Liu ,  Sridhar K Rabindran ,  Valery Sudakin ,  Hong Xiang ,  Pat G Brady ,  Nino Campobasso ,  Paris Ward ,  Jeffrey M Axten
Affiliations
  • 1. Oncology Research, GlaxoSmithKline, Collegeville, Pennsylvania 19426, United States. [email protected]
PMID: 21341675 DOI: 10.1021/jm101527u
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.