Exploitation of dihydroorotate dehydrogenase (DHODH) and p53 activation as therapeutic targets: A case study in polypharmacology

J Biol Chem. 2020 Dec 25;295(52):17935-17949. doi: 10.1074/jbc.RA119.012056. Epub 2020 Sep 8.

Abstract

The tenovins are a frequently studied class of compounds capable of inhibiting sirtuin activity, which is thought to result in increased acetylation and protection of the tumor suppressor p53 from degradation. However, as we and other laboratories have shown previously, certain tenovins are also capable of inhibiting autophagic flux, demonstrating the ability of these compounds to engage with more than one target. In this study, we present two additional mechanisms by which tenovins are able to activate p53 and kill tumor cells in culture. These mechanisms are the inhibition of a key enzyme of the de novo pyrimidine synthesis pathway, dihydroorotate dehydrogenase (DHODH), and the blockage of uridine transport into cells. These findings hold a 3-fold significance: first, we demonstrate that tenovins, and perhaps other compounds that activate p53, may activate p53 by more than one mechanism; second, that work previously conducted with certain tenovins as SirT1 inhibitors should additionally be viewed through the lens of DHODH inhibition as this is a major contributor to the mechanism of action of the most widely used tenovins; and finally, that small changes in the structure of a small molecule can lead to a dramatic change in the target profile of the molecule even when the phenotypic readout remains static.

Keywords: cell death; mitochondria; molecular modeling; molecular pharmacology; nucleoside/nucleotide biosynthesis; nucleoside/nucleotide transport; p53; tumor cell biology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetanilides / pharmacology*
  • Autophagy
  • Cell Proliferation
  • Dihydroorotate Dehydrogenase
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors*
  • Oxidoreductases Acting on CH-CH Group Donors / metabolism
  • Polypharmacology*
  • Sirtuin 1 / antagonists & inhibitors*
  • Thiourea / analogs & derivatives*
  • Thiourea / pharmacology
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Acetanilides
  • Dihydroorotate Dehydrogenase
  • Enzyme Inhibitors
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • tenovin-1
  • Oxidoreductases Acting on CH-CH Group Donors
  • SIRT1 protein, human
  • Sirtuin 1
  • Thiourea

Associated data

  • PDB/6GK0
  • PDB/2WV8