A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage
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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
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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
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