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

Research output: Contribution to journal › Article › peer-review

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
Article number	1107
Journal	Nature Communications
Volume	9
DOIs	https://doi.org/10.1038/s41467-018-03441-3
Publication status	Published - 16 Mar 2018

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Access to Document

10.1038/s41467-018-03441-3Licence: CC BY

Westwood_2018_NatComms_DHODHInhibitorp53_CCBY-VoR
Copyright 2018 the Authors. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Final published version, 2.2 MBLicence: CC BY

Cite this

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, Article 1107. https://doi.org/10.1038/s41467-018-03441-3

@article{c449edcce349434e90c7578f3e6f8696,

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 Andr{\'e}s Pastor-Fern{\'a}ndez 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 Anna-Lena Gustavsson 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",

note = "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{\textquoteright}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.",

year = "2018",

month = mar,

day = "16",

doi = "10.1038/s41467-018-03441-3",

language = "English",

volume = "9",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

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, A-L, 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, 1107. https://doi.org/10.1038/s41467-018-03441-3

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 - 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.

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.

UR - https://www.nature.com/articles/s41467-018-03441-3#Sec21

UR - https://www.scopus.com/pages/publications/85044243961

U2 - 10.1038/s41467-018-03441-3

DO - 10.1038/s41467-018-03441-3

M3 - Article

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

M1 - 1107

ER -

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

Abstract

UN SDGs

Access to Document

Other files and links

Fingerprint

Nicholas Westwood

Human Dihydroorotate Dehydrogenase in complex with novel inhibitor (PDB entry 6ET4)