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

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

Affiliation

  • 1 Oncology Research, GlaxoSmithKline, Collegeville, Pennsylvania 19426, United States. jesus.r.medina@gsk.com
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.

Figures