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A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage
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dc.contributor.author | Ladds, Marcus J.G.W. | |
dc.contributor.author | van Leeuwen, Ingeborg M.M. | |
dc.contributor.author | Drummond, Catherine J. | |
dc.contributor.author | Chu, Su | |
dc.contributor.author | Healy, Alan R. | |
dc.contributor.author | Popova, Gergana | |
dc.contributor.author | Pastor-Fernández, Andrés | |
dc.contributor.author | Mollick, Tanzina | |
dc.contributor.author | Darekar, Suhas | |
dc.contributor.author | Sedimbi, Saikiran K. | |
dc.contributor.author | Nekulova, Marta | |
dc.contributor.author | Sachweh, Marijke C.C. | |
dc.contributor.author | Campbell, Johanna | |
dc.contributor.author | Higgins, Maureen | |
dc.contributor.author | Tuck, Chloe | |
dc.contributor.author | Popa, Mihaela | |
dc.contributor.author | Safont, Mireia Mayoral | |
dc.contributor.author | Gelebart, Pascal | |
dc.contributor.author | Fandalyuk, Zinayida | |
dc.contributor.author | Thompson, Alastair M. | |
dc.contributor.author | Svensson, Richard | |
dc.contributor.author | Gustavsson, Anna-Lena | |
dc.contributor.author | Johansson, Lars | |
dc.contributor.author | Färnegårdh, Katarina | |
dc.contributor.author | Yngve, Ulrika | |
dc.contributor.author | Saleh, Aljona | |
dc.contributor.author | Haraldsson, Martin | |
dc.contributor.author | D'Hollander, Agathe C. A. | |
dc.contributor.author | Franco, Marcela | |
dc.contributor.author | Zhao, Yan | |
dc.contributor.author | Håkansson, Maria | |
dc.contributor.author | Walse, Björn | |
dc.contributor.author | Larsson, Karin | |
dc.contributor.author | Peat, Emma M. | |
dc.contributor.author | Pelechano, Vicent | |
dc.contributor.author | Lunec, John | |
dc.contributor.author | Vojtesek, Borivoj | |
dc.contributor.author | Carmena, Mar | |
dc.contributor.author | Earnshaw, William C. | |
dc.contributor.author | McCarthy, Anna R. | |
dc.contributor.author | Westwood, Nicholas J. | |
dc.contributor.author | Arsenian-Henriksson, Marie | |
dc.contributor.author | Lane, David P. | |
dc.contributor.author | Bhatia, Ravi | |
dc.contributor.author | McCormack, Emmet | |
dc.contributor.author | Laín, Sonia | |
dc.date.accessioned | 2018-03-26T13:30:07Z | |
dc.date.available | 2018-03-26T13:30:07Z | |
dc.date.issued | 2018-03-16 | |
dc.identifier | 252316970 | |
dc.identifier | c449edcc-e349-434e-90c7-578f3e6f8696 | |
dc.identifier | 85044243961 | |
dc.identifier | 000427591600007 | |
dc.identifier.citation | 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 . https://doi.org/10.1038/s41467-018-03441-3 | en |
dc.identifier.issn | 2041-1723 | |
dc.identifier.other | ORCID: /0000-0003-0630-0138/work/56424201 | |
dc.identifier.uri | https://hdl.handle.net/10023/13019 | |
dc.description | ML, 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. | en |
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. | |
dc.format.extent | 2305775 | |
dc.language.iso | eng | |
dc.relation.ispartof | Nature Communications | en |
dc.subject | QD Chemistry | en |
dc.subject | RM Therapeutics. Pharmacology | en |
dc.subject | DAS | en |
dc.subject | BDC | en |
dc.subject | R2C | en |
dc.subject | SDG 3 - Good Health and Well-being | en |
dc.subject.lcc | QD | en |
dc.subject.lcc | RM | en |
dc.title | A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage | en |
dc.type | Journal article | en |
dc.contributor.institution | University of St Andrews. School of Chemistry | en |
dc.contributor.institution | University of St Andrews. EaSTCHEM | en |
dc.contributor.institution | University of St Andrews. Biomedical Sciences Research Complex | en |
dc.identifier.doi | https://doi.org/10.1038/s41467-018-03441-3 | |
dc.description.status | Peer reviewed | en |
dc.identifier.url | https://www.nature.com/articles/s41467-018-03441-3#Sec21 | en |
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