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
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
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1107 (2018)
ER -