Please use this identifier to cite or link to this item:
https://doi.org/10.1038/s41467-018-03441-3
DC Field | Value | |
---|---|---|
dc.title | A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage | |
dc.contributor.author | Ladds, M.J.G.W | |
dc.contributor.author | Van Leeuwen, I.M.M | |
dc.contributor.author | Drummond, C.J | |
dc.date.accessioned | 2020-10-20T09:53:37Z | |
dc.date.available | 2020-10-20T09:53:37Z | |
dc.date.issued | 2018 | |
dc.identifier.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 | |
dc.identifier.issn | 2041-1723 | |
dc.identifier.uri | https://scholarbank.nus.edu.sg/handle/10635/178423 | |
dc.description.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). | |
dc.publisher | Nature Publishing Group | |
dc.rights | Attribution 4.0 International | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.source | Unpaywall 20201031 | |
dc.subject | antineoplastic agent | |
dc.subject | dihydroorotate dehydrogenase | |
dc.subject | dihydroorotate dehydrogenase inhibitor | |
dc.subject | hz 00 | |
dc.subject | hz 05 | |
dc.subject | nutlin 3 | |
dc.subject | protein p53 | |
dc.subject | unclassified drug | |
dc.subject | antineoplastic agent | |
dc.subject | enzyme inhibitor | |
dc.subject | indazole derivative | |
dc.subject | oxidoreductase | |
dc.subject | protein p53 | |
dc.subject | biodegradation | |
dc.subject | cancer | |
dc.subject | cell | |
dc.subject | chemical compound | |
dc.subject | crystal structure | |
dc.subject | enzyme | |
dc.subject | enzyme activity | |
dc.subject | growth | |
dc.subject | inhibitor | |
dc.subject | protein | |
dc.subject | tumor | |
dc.subject | animal cell | |
dc.subject | animal experiment | |
dc.subject | animal model | |
dc.subject | antineoplastic activity | |
dc.subject | Article | |
dc.subject | cancer cell | |
dc.subject | cancer combination chemotherapy | |
dc.subject | cell cycle S phase | |
dc.subject | cell killing | |
dc.subject | chirality | |
dc.subject | controlled study | |
dc.subject | crystal structure | |
dc.subject | drug identification | |
dc.subject | drug mechanism | |
dc.subject | enantiomer | |
dc.subject | enzyme inhibition | |
dc.subject | human | |
dc.subject | human cell | |
dc.subject | in vivo study | |
dc.subject | malignant neoplasm | |
dc.subject | melanoma | |
dc.subject | mouse | |
dc.subject | nonhuman | |
dc.subject | protein degradation | |
dc.subject | protein denaturation | |
dc.subject | protein synthesis | |
dc.subject | tumor growth | |
dc.subject | antagonists and inhibitors | |
dc.subject | cell cycle | |
dc.subject | cell proliferation | |
dc.subject | chemistry | |
dc.subject | drug effect | |
dc.subject | enzymology | |
dc.subject | genetics | |
dc.subject | metabolism | |
dc.subject | neoplasm | |
dc.subject | protein degradation | |
dc.subject | tumor cell line | |
dc.subject | Antineoplastic Agents | |
dc.subject | Cell Cycle | |
dc.subject | Cell Line, Tumor | |
dc.subject | Cell Proliferation | |
dc.subject | Enzyme Inhibitors | |
dc.subject | Humans | |
dc.subject | Indazoles | |
dc.subject | Neoplasms | |
dc.subject | Oxidoreductases Acting on CH-CH Group Donors | |
dc.subject | Proteolysis | |
dc.subject | Tumor Suppressor Protein p53 | |
dc.type | Article | |
dc.contributor.department | MEDICINE | |
dc.description.doi | 10.1038/s41467-018-03441-3 | |
dc.description.sourcetitle | Nature Communications | |
dc.description.volume | 9 | |
dc.description.issue | 1 | |
dc.description.page | 1107 | |
dc.published.state | published | |
Appears in Collections: | Staff Publications Elements |
Show simple item record
Files in This Item:
File | Description | Size | Format | Access Settings | Version | |
---|---|---|---|---|---|---|
10_1038_s41467-018-03441-3.pdf | 2.48 MB | Adobe PDF | OPEN | None | View/Download |
This item is licensed under a Creative Commons License