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 and Sonia Laín ()
Additional contact information
Marcus J. G. W. Ladds: Karolinska Institutet
Ingeborg M. M. van Leeuwen: Karolinska Institutet
Catherine J. Drummond: Karolinska Institutet
Su Chu: Comprehensive Cancer Center
Alan R. Healy: University of St. Andrews and EaStCHEM
Gergana Popova: Karolinska Institutet
Andrés Pastor Fernández: Karolinska Institutet
Tanzina Mollick: Karolinska Institutet
Suhas Darekar: Karolinska Institutet
Saikiran K. Sedimbi: Karolinska Institutet
Marta Nekulova: Karolinska Institutet
Marijke C. C. Sachweh: Karolinska Institutet
Johanna Campbell: University of Dundee, Ninewells Hospital and Medical School
Maureen Higgins: University of Dundee, Ninewells Hospital and Medical School
Chloe Tuck: Karolinska Institutet
Mihaela Popa: University of Bergen
Mireia Mayoral Safont: University of Bergen
Pascal Gelebart: University of Bergen
Zinayida Fandalyuk: University of Bergen
Alastair M. Thompson: Holcombe Boulevard
Richard Svensson: Uppsala University
Anna-Lena Gustavsson: Karolinska Institutet
Lars Johansson: Karolinska Institutet
Katarina Färnegårdh: Science for Life Laboratory
Ulrika Yngve: Uppsala University
Aljona Saleh: Uppsala University
Martin Haraldsson: Science for Life Laboratory
Agathe C. A. D’Hollander: University of St. Andrews and EaStCHEM
Marcela Franco: Karolinska Institutet
Yan Zhao: Newcastle University
Maria Håkansson: Medicon Village
Björn Walse: Medicon Village
Karin Larsson: Karolinska Institutet
Emma M. Peat: University of Edinburgh
Vicent Pelechano: Karolinska Institutet
John Lunec: Newcastle University
Borivoj Vojtesek: RECAMO, Masaryk Memorial Cancer Institute
Mar Carmena: University of Edinburgh
William C. Earnshaw: University of Edinburgh
Anna R. McCarthy: Karolinska Institutet
Nicholas J. Westwood: University of St. Andrews and EaStCHEM
Marie Arsenian-Henriksson: Karolinska Institutet
David P. Lane: Karolinska Institutet
Ravi Bhatia: Comprehensive Cancer Center
Emmet McCormack: University of Bergen
Sonia Laín: Karolinska Institutet

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03441-3

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