A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage
MetadataShow full item record
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.
Ladds , M J G W , van Leeuwen , I M M , Drummond , C J , Chu , S , Healy , A R , Popova , G , Pastor-Fernández , A , Mollick , T , Darekar , S , Sedimbi , S K , Nekulova , M , Sachweh , M C C , Campbell , J , Higgins , M , Tuck , C , Popa , M , Safont , M M , Gelebart , P , Fandalyuk , Z , Thompson , A M , Svensson , R , Gustavsson , A-L , Johansson , L , Färnegårdh , K , Yngve , U , Saleh , A , Haraldsson , M , D'Hollander , A C A , Franco , M , Zhao , Y , Håkansson , M , Walse , B , Larsson , K , Peat , E M , Pelechano , V , Lunec , J , Vojtesek , B , Carmena , M , Earnshaw , W C , McCarthy , A R , Westwood , N J , Arsenian-Henriksson , M , Lane , D P , Bhatia , R , McCormack , E & Laín , S 2018 , ' A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage ' Nature Communications , vol. 9 , 1107 . DOI: 10.1038/s41467-018-03441-3
Copyright 2018 the Authors. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
DescriptionML, CD, IvL, GP, TM, SD, MS, APF, CT, DL, MAH, KL and SL: project grants from the Swedish Research Council, the Swedish Cancer Society and the Swedish Childhood Cancer Foundation. MHi and JC: Cancer Research UK (C8/A6613). MC, EP and WE: Wellcome Trust (073915). MN and BV: projects MEYS-NPS-LO1413 and GACR P206/12/G151. EMC, MP, MMS, ZF and PG: Norwegian Cancer Society (182735, 732200) and Helse Vest (911884, 911789). RB and SC: NIH (R01 CA95684), the Leukemia and Lymphoma Society and the Waxman Foundation. NW, AH, Ad’H: Cancer Research UK (C21383/A6950) and Engineering and Physical Sciences Research Council Doctoral Training Program. JL and YZ: Cancer Research UK (C240/A15751). MH and BW: SARomics Biostructures ABUY, KF: DDDP SciLife, Sweden. LJ, MHa, RS and A-LG: CBCS, Sweden. VP: SciLife fellowship. AT: Breast Cancer Research Scotland
Items in the St Andrews Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.