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. ThompsonRichard 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

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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.

Original languageEnglish
Article number1107
Pages (from-to)1-14
Number of pages14
JournalNature Communications
Volume9
DOIs
Publication statusPublished - 16 Mar 2018

Keywords

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

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  • Publisher Correction: A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage

    Ladds, M. J. G. W., Van Leeuwen, I. M. M., Drummond, C. J., Chu, S., Healy, A. R., Popova, G., Pastor Fernández, A., Mollick, T., Darekar, S., Sedimbi, S. K., Nekulova, M., Sachweh, M. C. C., Campbell, J., Higgins, M., Tuck, C., Popa, M., Safont, M. M., Gelebart, P., Fandalyuk, Z., Thompson, A. M. & 26 others, Svensson, R., Gustavsson, A. L., Johansson, L., Färnegårdh, K., Yngve, U., Saleh, A., Haraldsson, M., D'Hollander, A. C. A., Franco, M., Zhao, Y., Håkansson, M., Walse, B., Larsson, K., Peat, E. M., Pelechano, V., Lunec, J., Vojtesek, B., Carmena, M., Earnshaw, W. C., McCarthy, A. R., Westwood, N. J., Arsenian-Henriksson, M., Lane, D. P., Bhatia, R., McCormack, E. & Laín, S., 22 May 2018, In : Nature Communications. 9, 1, p. 2071 2071.

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