A DHODH Inhibitor Increases p53 Synthesis and Enhances Tumor Cell Killing by p53 Degradation Blockage

A DHODH Inhibitor Increases p53 Synthesis and Enhances Tumor Cell Killing by p53 Degradation Blockage
Title:
A DHODH Inhibitor Increases p53 Synthesis and Enhances Tumor Cell Killing by p53 Degradation Blockage
Other Titles:
Nature Communications
Publication Date:
16 March 2018
Citation:
Ladds, M.J.G.W., van Leeuwen, I.M.M., Drummond, C.J. et al. A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage. Nat Commun 9, 1107 (2018). https://doi.org/10.1038/s41467-018-03441-3
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.
License type:
http://creativecommons.org/licenses/by/4.0/
Funding Info:
M.J.G.W.L., C.J.D., I.M.M.v.L., G.P., T.M., S.D., M.C.C. S., A.P.-F., C.T., D.P.L., M.A.H., K.L., and S.L.: project grants from the Swedish Research Council, the Swedish Cancer Society and the Swedish Childhood Cancer Foundation. M.H. and J.C.: Cancer Research UK (C8/A6613). M.C., E.P., and W.C.E.: Wellcome Trust (073915). M.N. and B.V.: projects MEYS-NPS-LO1413 and GACR P206/12/G151. E.M.C., M.P., M.M.S., Z.F., and P.G.: Norwegian Cancer Society (182735, 732200) and Helse Vest (911884, 911789). R.B. and S.C.: NIH (R01 CA95684), the Leukemia and Lymphoma Society and the Waxman Foundation. N.J.W., A.R.H., A.C.A.d’H.: Cancer Research UK (C21383/A6950) and Engineering and Physical Sciences Research Council Doctoral Training Program. J.L. and Y.Z.: Cancer Research UK (C240/A15751). M.H. and B.W.: SARomics Biostructures AB. U.Y., K.F.: DDDP SciLife, Sweden. L.J., M.H., R.S., and A.-L.G.: CBCS, Sweden. VP: SciLife fellowship. AMT: Breast Cancer Research Scotland
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ISSN:
2041-1723
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