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

作者：Ladds Marcus J G W; van Leeuwen Ingeborg M M; Drummond Catherine J; Chu Su; Healy Alan R; Popova Gergana; Fernandez Andres 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; Svensson Richard; Gustavsson Anna Lena; Johansson Lars; Farnegardh Katarina; Yngve Ulrika

来源：Nature Communications, 2018, 9(1): 1107.

DOI：10.1038/s41467-018-03441-3

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.

• 出版日期2018-3-16