Ladds MJGW, van Leeuwen IMM, Drummond CJ, Chu S, Healy AR, Popova G, Pastor Fernández 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
Nat Commun 9 (1) 1107 [2018-03-16; online 2018-03-16]
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.