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

Marcus J.G.W. Ladds; Ingeborg M.M. Van Leeuwen; Catherine J. Drummond; Su Chu; Alan R. Healy; Gergana Popova; Andrés Pastor Fernández; Tanzina Mollick; Suhas Darekar; Saikiran K. Sedimbi; Marta Nekulova; Marijke C.C. Sachweh; Johanna Campbell; Maureen Higgins; Chloe Tuck; Mihaela Popa; Mireia Mayoral Safont; Pascal Gelebart; Zinayida Fandalyuk; Alastair M. Thompson; Richard Svensson; Anna Lena Gustavsson; Lars Johansson; Katarina Färnegårdh; Ulrika Yngve; Aljona Saleh; Martin Haraldsson; Agathe C.A. D'Hollander; Marcela Franco; Yan Zhao; Maria Håkansson; Björn Walse; Karin Larsson; Emma M. Peat; Vicent Pelechano; John Lunec; Borivoj Vojtesek; Mar Carmena; William C. Earnshaw; Anna R. McCarthy; Nicholas J. Westwood; Marie Arsenian-Henriksson; David P. Lane; Ravi Bhatia; Emmet McCormack; Sonia Laín

doi:10.1038/s41467-018-03441-3

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

Marcus J.G.W. Ladds, Ingeborg M.M. Van Leeuwen, Catherine J. Drummond, Su Chu, Alan R. Healy, Gergana Popova, Andrés Pastor Fernández, Tanzina Mollick, Suhas Darekar, Saikiran K. Sedimbi, Marta Nekulova, Marijke C.C. Sachweh, Johanna Campbell, Maureen Higgins, Chloe Tuck, Mihaela Popa, Mireia Mayoral Safont, Pascal Gelebart, Zinayida Fandalyuk, Alastair M. ThompsonRichard Svensson, Anna Lena Gustavsson, Lars Johansson, Katarina Färnegårdh, Ulrika Yngve, Aljona Saleh, Martin Haraldsson, Agathe C.A. D'Hollander, Marcela Franco, Yan Zhao, Maria Håkansson, Björn Walse, Karin Larsson, Emma M. Peat, Vicent Pelechano, John Lunec, Borivoj Vojtesek, Mar Carmena, William C. Earnshaw, Anna R. McCarthy, Nicholas J. Westwood, Marie Arsenian-Henriksson, David P. Lane, Ravi Bhatia, Emmet McCormack, Sonia Laín

Surgical Oncology

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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.

Original language	English (US)
Article number	1107
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-03441-3
State	Published - Dec 1 2018

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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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., ... Laín, S. (2018). A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage. Nature communications, 9(1), Article 1107. https://doi.org/10.1038/s41467-018-03441-3

Ladds, MJGW, Van Leeuwen, IMM, Drummond, CJ, Chu, S, Healy, AR, Popova, G, Pastor Fernández, A, Mollick, T, Darekar, S, Sedimbi, SK, Nekulova, M, Sachweh, MCC, Campbell, J, Higgins, M, Tuck, C, Popa, M, Safont, MM, Gelebart, P, Fandalyuk, Z, Thompson, AM, Svensson, R, Gustavsson, AL, Johansson, L, Färnegårdh, K, Yngve, U, Saleh, A, Haraldsson, M, D'Hollander, ACA, Franco, M, Zhao, Y, Håkansson, M, Walse, B, Larsson, K, Peat, EM, Pelechano, V, Lunec, J, Vojtesek, B, Carmena, M, Earnshaw, WC, McCarthy, AR, Westwood, NJ, Arsenian-Henriksson, M, Lane, DP, 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, no. 1, 1107. https://doi.org/10.1038/s41467-018-03441-3

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title = "A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage",

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.",

author = "Ladds, {Marcus J.G.W.} and {Van Leeuwen}, {Ingeborg M.M.} and Drummond, {Catherine J.} and Su Chu and Healy, {Alan R.} and Gergana Popova and {Pastor Fern{\'a}ndez}, Andr{\'e}s and Tanzina Mollick and Suhas Darekar and Sedimbi, {Saikiran K.} and Marta Nekulova and Sachweh, {Marijke C.C.} and Johanna Campbell and Maureen Higgins and Chloe Tuck and Mihaela Popa and Safont, {Mireia Mayoral} and Pascal Gelebart and Zinayida Fandalyuk and Thompson, {Alastair M.} and Richard Svensson and Gustavsson, {Anna Lena} and Lars Johansson and Katarina F{\"a}rneg{\aa}rdh and Ulrika Yngve and Aljona Saleh and Martin Haraldsson and D'Hollander, {Agathe C.A.} and Marcela Franco and Yan Zhao and Maria H{\aa}kansson and Bj{\"o}rn Walse and Karin Larsson and Peat, {Emma M.} and Vicent Pelechano and John Lunec and Borivoj Vojtesek and Mar Carmena and Earnshaw, {William C.} and McCarthy, {Anna R.} and Westwood, {Nicholas J.} and Marie Arsenian-Henriksson and Lane, {David P.} and Ravi Bhatia and Emmet McCormack and Sonia La{\'i}n",

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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 - 2018/12/1

Y1 - 2018/12/1

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.

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

Abstract

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