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https://doi.org/10.1038/s41467-018-03441-3
Title: | A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage | Authors: | Ladds, M.J.G.W Van Leeuwen, I.M.M Drummond, C.J |
Keywords: | antineoplastic agent dihydroorotate dehydrogenase dihydroorotate dehydrogenase inhibitor hz 00 hz 05 nutlin 3 protein p53 unclassified drug antineoplastic agent enzyme inhibitor indazole derivative oxidoreductase protein p53 biodegradation cancer cell chemical compound crystal structure enzyme enzyme activity growth inhibitor protein tumor animal cell animal experiment animal model antineoplastic activity Article cancer cell cancer combination chemotherapy cell cycle S phase cell killing chirality controlled study crystal structure drug identification drug mechanism enantiomer enzyme inhibition human human cell in vivo study malignant neoplasm melanoma mouse nonhuman protein degradation protein denaturation protein synthesis tumor growth antagonists and inhibitors cell cycle cell proliferation chemistry drug effect enzymology genetics metabolism neoplasm protein degradation tumor cell line Antineoplastic Agents Cell Cycle Cell Line, Tumor Cell Proliferation Enzyme Inhibitors Humans Indazoles Neoplasms Oxidoreductases Acting on CH-CH Group Donors Proteolysis Tumor Suppressor Protein p53 |
Issue Date: | 2018 | Publisher: | Nature Publishing Group | Citation: | Ladds, M.J.G.W, Van Leeuwen, I.M.M, Drummond, C.J (2018). A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage. Nature Communications 9 (1) : 1107. ScholarBank@NUS Repository. https://doi.org/10.1038/s41467-018-03441-3 | Rights: | Attribution 4.0 International | 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. © 2018 The Author(s). | Source Title: | Nature Communications | URI: | https://scholarbank.nus.edu.sg/handle/10635/178423 | ISSN: | 2041-1723 | DOI: | 10.1038/s41467-018-03441-3 | Rights: | Attribution 4.0 International |
Appears in Collections: | Staff Publications Elements |
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