In vitro cytotoxicity screening to identify novel anti-osteosarcoma therapeutics targeting pyruvate dehydrogenase kinase 2

Bioorg Med Chem Lett. 2019 Oct 15;29(20):126665. doi: 10.1016/j.bmcl.2019.126665. Epub 2019 Sep 3.

Abstract

Pyruvate dehydrogenase kinases (PDKs) act as negative modulator of mitochondrial pyruvate dehydrogenase complex (PDC) and play a crucial role in the regulation of oxidative glycolysis, which recently have been considered as a potential drug target for varying types of cancer and diabetes. Herein, we describe the discovery and biological validation of novel anti-osteosarcoma therapeutics targeting PDK2. We identified 14 anti-osteosarcoma compounds from an in-house small molecule library, which were then evaluated in a PDK2 kinase inhibition assay. We found that compounds with 2-((4-oxo-6-((4-phenylpiperazin-1-yl)methyl)-4H-pyran-3-yl)oxy)acetamide moiety showed promising inhibitory potencies to PDK2. Especial for 12, which bound to PDK2 with a Kd value of 2.3 µM, and inhibited PDK2 activity with an EC50 value of 1.1 µM. In addition, 12 selectively inhibited PDK2, the selectivity indexes are 10.6, 22.0, and 60.9 for PDK2 as compared to PDK1, 2 and 4, respectively. The MTT assay suggested that 12 reduced MG-63 cancer cell proliferation with an IC50 value of 4.7 µM. All these observations indicated that 12 was a novel anti-osteosarcoma therapeutic, which deserved for further investigation.

Keywords: Anticancer; Cancer metabolism; Pyruvate dehydrogenase kinase 2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetamides / chemistry*
  • Acetamides / pharmacology
  • Amino Acids / chemistry
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Bone Neoplasms / drug therapy
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Screening Assays, Antitumor
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Molecular Targeted Therapy
  • Osteosarcoma / drug therapy*
  • Piperazines / chemistry
  • Piperazines / pharmacology*
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase / metabolism*
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / pharmacology
  • Structure-Activity Relationship

Substances

  • Acetamides
  • Amino Acids
  • Antineoplastic Agents
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Small Molecule Libraries