TY - JOUR
T1 - A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage
AU - Ladds, Marcus J.G.W.
AU - Van Leeuwen, Ingeborg M.M.
AU - Drummond, Catherine J.
AU - Chu, Su
AU - Healy, Alan R.
AU - Popova, Gergana
AU - Pastor Fernández, Andrés
AU - Mollick, Tanzina
AU - Darekar, Suhas
AU - Sedimbi, Saikiran K.
AU - Nekulova, Marta
AU - Sachweh, Marijke C.C.
AU - Campbell, Johanna
AU - Higgins, Maureen
AU - Tuck, Chloe
AU - Popa, Mihaela
AU - Safont, Mireia Mayoral
AU - Gelebart, Pascal
AU - Fandalyuk, Zinayida
AU - Thompson, Alastair M.
AU - Svensson, Richard
AU - Gustavsson, Anna Lena
AU - Johansson, Lars
AU - Färnegårdh, Katarina
AU - Yngve, Ulrika
AU - Saleh, Aljona
AU - Haraldsson, Martin
AU - D'Hollander, Agathe C.A.
AU - Franco, Marcela
AU - Zhao, Yan
AU - Håkansson, Maria
AU - Walse, Björn
AU - Larsson, Karin
AU - Peat, Emma M.
AU - Pelechano, Vicent
AU - Lunec, John
AU - Vojtesek, Borivoj
AU - Carmena, Mar
AU - Earnshaw, William C.
AU - McCarthy, Anna R.
AU - Westwood, Nicholas J.
AU - Arsenian-Henriksson, Marie
AU - Lane, David P.
AU - Bhatia, Ravi
AU - McCormack, Emmet
AU - Laín, Sonia
N1 - The authors would like to acknowledge ChemAxon (www.chemaxon.com) for providing an academic license to their cheminformatics software and Sweden Contract In vivo Design AB for performing in vivo PK studies. We also thank Annika Lindquist, Eliane Hesse, Melina Vallbracht, Levin Schulze, Amparo Martínez Pérez, and Antonio Ramírez Fernández for technical support, as well as EPRSC National Mass Spectrometry Service Centre (Swansea) for analytical data. Financial Support: 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.
PY - 2018/3/16
Y1 - 2018/3/16
N2 - 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.
AB - 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.
KW - Drug development
KW - Mechanism of action
KW - Small molecules
KW - Target identification
U2 - 10.1038/s41467-018-03441-3
DO - 10.1038/s41467-018-03441-3
M3 - Article
C2 - 29549331
AN - SCOPUS:85044243961
SN - 2041-1723
VL - 9
SP - 1
EP - 14
JO - Nature Communications
JF - Nature Communications
M1 - 1107
ER -