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. Epub 2011 Feb 22.

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.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • Drug Screening Assays, Antitumor
  • Indazoles / chemical synthesis*
  • Indazoles / chemistry
  • Indazoles / pharmacology
  • Mice
  • Mice, SCID
  • Models, Molecular
  • Molecular Structure
  • Morpholines / chemical synthesis*
  • Morpholines / chemistry
  • Morpholines / pharmacology
  • Neoplasm Transplantation
  • Phosphorylation
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Piperidines / pharmacology
  • Protein Binding
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Stereoisomerism
  • Structure-Activity Relationship
  • Transplantation, Heterologous

Substances

  • Antineoplastic Agents
  • Indazoles
  • Morpholines
  • Pdk1 protein, mouse
  • Piperidines
  • Pyrimidines
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Protein Serine-Threonine Kinases

Associated data

  • PDB/3QCQ
  • PDB/3QCS
  • PDB/3QCX
  • PDB/3QCY
  • PDB/3QD0
  • PDB/3QD3
  • PDB/3QD4