Poster Presentation 30th Lorne Cancer Conference 2018

Discovery of a novel DHODH inhibitor capable of increasing p53 synthesis and enhancing tumour cell killing by p53 degradation blockage (#189)

Marcus JGW Ladds 1 , Ingeborg MM van Leeuwen 1 , Catherine J Drummond 1 , Su Chu 2 , Alan R Healy 3 , Gergana Popova 1 , Andrés Pastor-Fernández 1 , Tanzina Mollick 1 , Suhas Darekar 1 , Saikiran K Sedimbi 1 4 , Marta Nekulova 1 5 , Marijke CC Sachweh 1 , Johanna Campbell 6 , Maureen Higgins 6 , Chloe Tuck 1 , Mihaela Popa 7 , Mireia Mayoral Safont 7 , Pascal Gelebart 7 , Zinayida Fandalyuk 7 , Alastair M Thompson 8 , Richard Svensson 9 , Anna-Lena Gustavsson 10 , Lars Johansson 10 , Katarina Färnegårdh 11 , Ulrika Yngve 12 , Aljona Saleh 12 , Martin Haraldsson 11 , Agathe CA D'Hollander 3 , Marcela Franco 1 , Yan Zhao 13 , Maria Håkansson 14 , Björn Walse 14 , Karin Larsson 1 , Emma M Peat 15 , Vicent Pelechano 16 , John Lunec 13 , Borivoj Vojtesek 5 , Mar Carmena 15 , William C Earnshaw 15 , Nicholas J Westwood 3 , Marie Arsenian Henriksson 1 , David P Lane 1 4 , Ravi Bhatia 2 , Emmet McCormack 7 17 , Sonia Laín 1 4
  1. Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
  2. Devision of Hematology & Oncology, Comprehensive Cancer Center (CCC), University of Alabama at Birmingham (UAB), Birmingham, AL, United States of America
  3. School of Chemistry and Biomedical Sciences Research Complex, University of St. Andrews, St. Andrews, Fife, Scotland, United Kingdom
  4. SciLifeLab, Karolinska Institutet, Stockholm, Sweden
  5. RECAMO, Masaryk Memorial Cancer Institute, Brno, Czech Republic
  6. Centre for Oncology and Molecular Medicine, University of Dundee, Dundee, Tayside, Scotland, United Kingdom
  7. Centre for Cancer Biomarkers (CCBIO), Department of Clinical Science, University of Bergen, Bergen, Norway
  8. Department of Breast Surgical Oncology, MD Anderson Cancer Center, Houston, TX, United States of America
  9. Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Department of Pharmacy, Uppsala University, Uppsala, Sweden
  10. Chemical Biology Consortium Sweden (LCBKI), SciLifeLab, Division of Translational Medicine and Chemical Biology, MBB, Karolinska Institutet, Stockholm, Sweden
  11. Drug Discovery and Development Platform (DDDP), SciLifeLab, Stockholm, Sweden
  12. Department of Medicinal Chemistry, SciLifeLab, Uppsala University, Uppsala, Sweden
  13. Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle, United Kingdom
  14. SARomics Biostructures, Lund, Sweden
  15. The Wellcome Trust Centre for Cell Biology, Institute of Cell Biology, University of Edinburgh, Edinburgh, Scotland, United Kingdom
  16. SciLifeLab, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
  17. Department of Medicine, Haematology Section, Haukeland University Hospital, Bergen, Norway

Here we report the identification of over 100 small-molecules activating the tumour suppressor p53 in cells. Of these, we chose to elucidate the mechanism of action of a chiral tetrahydroindazole, HZ00. By analysing a series of cellular responses to HZ00, we deduced that its active enantiomer, (R)-HZ00, inhibits dihydroorotate-dehydrogenase (DHODH). The basis for the chiral specificity of HZ05, a more potent analogue of HZ00, is revealed by the crystal structure of the (R)-HZ05/DHODH complex. In addition to the HZ series, twelve DHODH inhibitor chemotypes were also identified amongst the p53 activators listed, which suggests that DHODH is a remarkably frequent target for structurally diverse compounds. We observed during target deconvolution that HZ compounds accumulate cancer cells in S-phase, increase p53 synthesis, and synergise to reduce tumour growth in vivo when co-administered with an inhibitor of p53 degradation. We therefore propose a new strategy to promote cancer cell killing by p53 instead of its reversible cell cycle arresting effect.