A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage

Academic Article

Abstract

  • ¬© 2018 The Author(s). The development of non-genotoxic therapies that activate wild-Type p53 in tumors is of great interest since the discovery of p53 as a tumor suppressor. Here we report the identification of over 100 small-molecules activating p53 in cells. We elucidate the mechanism of action of a chiral tetrahydroindazole (HZ00), and through target deconvolution, we deduce that its active enantiomer (R)-HZ00, inhibits dihydroorotate dehydrogenase (DHODH). The chiral specificity of HZ05, a more potent analog, is revealed by the crystal structure of the (R)-HZ05/DHODH complex. Twelve other DHODH inhibitor chemotypes are detailed among the p53 activators, which identifies DHODH as a frequent target for structurally diverse compounds. We observe that HZ compounds accumulate cancer cells in S-phase, increase p53 synthesis, and synergize with an inhibitor of p53 degradation to reduce tumor growth in vivo. We, therefore, propose a strategy to promote cancer cell killing by p53 instead of its reversible cell cycle arresting effect.
  • Digital Object Identifier (doi)

    Author List

  • Ladds MJGW; Van Leeuwen IMM; Drummond CJ; Chu S; Healy AR; Popova G; Pastor Fern√°ndez A; Mollick T; Darekar S; Sedimbi SK
  • Volume

  • 9
  • Issue

  • 1