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A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53degradation blockage

Lookup NU author(s): Dr Yan Zhao, Professor John Lunec

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.


Publication metadata

Author(s): Ladds MJGW, van Leeuwen IMM, Drummond CJ, Chu S, Healy AR, Popova G, Pastor Fernandez A, Mollick T, Darekar S, Sedimbi SK, Nekulova M, Sachweh MCC, Campbell J, Higgins M, Tuck C, Popa M, Safont MM, Gelebart P, Fandalyuk Z, Thompson AM, Svensson R, Gustavsson AL, Johansson L, Färnegårdh K, Yngve U, Saleh A, Haraldsson M, D'Hollander ACA, Franco M, Zhao Y, Håkansson M, Walse B, Larsson K, Peat EM, Pelechano V, Lunec J, Vojtesek B, Carmena M, Earnshaw WC, McCarthy AR, Westwood NJ, Arsenian-Henriksson M, Lane DP, Bhatia R, McCormack E, Laín S

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2018

Volume: 9

Online publication date: 16/03/2018

Acceptance date: 13/02/2018

Date deposited: 05/04/2018

ISSN (electronic): 2041-1723

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/s41467-018-03441-3

DOI: 10.1038/s41467-018-03441-3

PubMed id: 29549331


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