Nature Communications (Mar 2018)

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

  • Marcus J. G. W. Ladds,
  • Ingeborg M. M. van Leeuwen,
  • Catherine J. Drummond,
  • Su Chu,
  • Alan R. Healy,
  • Gergana Popova,
  • Andrés Pastor Fernández,
  • Tanzina Mollick,
  • Suhas Darekar,
  • Saikiran K. Sedimbi,
  • Marta Nekulova,
  • Marijke C. C. Sachweh,
  • Johanna Campbell,
  • Maureen Higgins,
  • Chloe Tuck,
  • Mihaela Popa,
  • Mireia Mayoral Safont,
  • Pascal Gelebart,
  • Zinayida Fandalyuk,
  • Alastair M. Thompson,
  • Richard Svensson,
  • Anna-Lena Gustavsson,
  • Lars Johansson,
  • Katarina Färnegårdh,
  • Ulrika Yngve,
  • Aljona Saleh,
  • Martin Haraldsson,
  • Agathe C. A. D’Hollander,
  • Marcela Franco,
  • Yan Zhao,
  • Maria Håkansson,
  • Björn Walse,
  • Karin Larsson,
  • Emma M. Peat,
  • Vicent Pelechano,
  • John Lunec,
  • Borivoj Vojtesek,
  • Mar Carmena,
  • William C. Earnshaw,
  • Anna R. McCarthy,
  • Nicholas J. Westwood,
  • Marie Arsenian-Henriksson,
  • David P. Lane,
  • Ravi Bhatia,
  • Emmet McCormack,
  • Sonia Laín

DOI
https://doi.org/10.1038/s41467-018-03441-3
Journal volume & issue
Vol. 9, no. 1
pp. 1 – 14

Abstract

Read online

Abstract 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.