학술논문
A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage
Document Type
article
Author
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
Source
Nature Communications, Vol 9, Iss 1, Pp 1-14 (2018)
Subject
Language
English
ISSN
2041-1723
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.