期刊
NATURE COMMUNICATIONS
卷 9, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-03441-3
关键词
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资金
- Swedish Research Council
- Swedish Cancer Society
- Swedish Childhood Cancer Foundation
- Cancer Research UK [C8/A6613, C21383/A6950, C240/A15751]
- Wellcome Trust [073915]
- GACR [P206/12/G151]
- Norwegian Cancer Society [182735, 732200]
- Helse Vest [911884, 911789]
- NIH [R01 CA95684]
- Leukemia and Lymphoma Society
- Waxman Foundation
- Engineering and Physical Sciences Research Council
- [MEYS-NPS-LO1413]
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.
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