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

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  • 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
  • Anna R McCarthy
  • Marie Arsenian-Henriksson
  • Ravi Bhatia
  • Emmet McCormack
  • Sonia Laín

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Original languageEnglish
Article number1107 (2018)
Number of pages14
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 16 Mar 2018

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.

    Research areas

  • Drug development, Mechanism of action, Small molecules, Target identification

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