Generation of a Selective Small Molecule Inhibitor of the CBP/p300 Bromodomain for Leukemia Therapy

  • Cancer Res. 2015 Dec 1;75(23):5106-5119. doi: 10.1158/0008-5472.CAN-15-0236.
Sarah Picaud   #  1  2 ,  Oleg Fedorov   #  1  3 ,  Angeliki Thanasopoulou   #  4 ,  Katharina Leonards   #  4 ,  Katherine Jones  5 ,  Julia Meier  1  3 ,  Heidi Olzscha  6 ,  Octovia Monteiro  1  3 ,  Sarah Martin  1  3 ,  Martin Philpott  1  3 ,  Anthony Tumber  1  3 ,  Panagis Filippakopoulos  1  2 ,  Clarence Yapp  3 ,  Christopher Wells  1  3 ,  Ka Hing Che  7 ,  Andrew Bannister  7 ,  Samuel Robson  7 ,  Umesh Kumar  5 ,  Nigel Parr  5 ,  Kevin Lee  5 ,  Dave Lugo  8 ,  Philip Jeffrey  8 ,  Simon Taylor  8 ,  Matteo L Vecellio  3 ,  Chas Bountra  1 ,  Paul E Brennan  1  3 ,  Alison O'Mahony  9 ,  Sharlene Velichko  9 ,  Susanne Müller  1  3 ,  Duncan Hay  3 ,  Danette L Daniels  10 ,  Marjeta Urh  10 ,  Nicholas B La Thangue  6 ,  Tony Kouzarides  7 ,  Rab Prinjha  5 ,  Jürg Schwaller  4 ,  Stefan Knapp  1  3
Affiliations
  • 1. Nuffield Department of Clinical Medicine, University of Oxford, Structural Genomics Consortium, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
  • 2. Nuffield Department of Clinical Medicine, University of Oxford, Ludwig Institute for Cancer Research (LICR), Roosevelt Drive, Oxford OX3 7DQ, UK.
  • 3. Nuffield Department of Clinical Medicine, University of Oxford, Target Discovery Institute (TDI), Roosevelt Drive, Oxford OX3 7BN, UK.
  • 4. Laboratory of Childhood Leukemia, Department of Biomedicine, University of Basel and Basel University Children's Hospital, Hebelstrasse 20 CH - 4031 Basel, Switzerland.
  • 5. Epinova DPU, Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage SG1 2NY, UK.
  • 6. Laboratory of Cancer Biology, Department of Oncology, Medical Sciences Division, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK.
  • 7. Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge CB2 1QN, UK.
  • 8. Experimental Medicines Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, UK.
  • 9. BioSeek Division of DiscoveRx Corporation, 310 Utah Street, Suite 100, South San Francisco, CA, 94080, USA.
  • 10. Promega Corporation, 2800 Woods Hollow Road, Madison, Wisconsin, U.S.A 53711.
  • # Contributed equally.
PMID: 26552700 DOI: 10.1158/0008-5472.CAN-15-0236
Abstract

The histone acetyltransferases CBP/p300 are involved in recurrent leukemia-associated chromosomal translocations and are key regulators of cell growth. Therefore, efforts to generate inhibitors of CBP/p300 are of clinical value. We developed a specific and potent acetyl-lysine competitive protein-protein interaction inhibitor, I-CBP112, that targets the CBP/p300 bromodomains. Exposure of human and mouse leukemic cell lines to I-CBP112 resulted in substantially impaired colony formation and induced cellular differentiation without significant cytotoxicity. I-CBP112 significantly reduced the leukemia-initiating potential of MLL-AF9(+) Acute Myeloid Leukemia cells in a dose-dependent manner in vitro and in vivo. Interestingly, I-CBP112 increased the cytotoxic activity of BET bromodomain inhibitor JQ1 as well as doxorubicin. Collectively, we report the development and preclinical evaluation of a novel, potent inhibitor targeting CBP/p300 bromodomains that impairs aberrant self-renewal of leukemic cells. The synergistic effects of I-CBP112 and current standard therapy (doxorubicin) as well as emerging treatment strategies (BET inhibition) provide new opportunities for combinatorial treatment of leukemia and potentially other cancers.

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