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- Title
A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage.
- Authors
Ladds, Marcus J. G. W.; van Leeuwen, Ingeborg M. M.; Drummond, Catherine J.; Su Chu; Healy, Alan R.; Popova, Gergana; Fernández, Andrés Pastor; Mollick, Tanzina; Darekar, Suhas; Sedimbi, Saikiran K.; Nekulova, Marta; Sachweh, Marijke C. C.; Campbell, Johanna; Higgins, Maureen; Tuck, Chloe; Popa, Mihaela; Safont, Mireia Mayoral; Gelebart, Pascal; Fandalyuk, Zinayida; Thompson, Alastair M.
- 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.
- Subjects
P53 protein; TUMOR growth; DIHYDROOROTATE dehydrogenase; CANCER cells; CELL cycle; BIOCHEMICAL mechanism of action; P53 antioncogene
- Publication
Nature Communications, 2018, Vol 9, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-018-03441-3