2. Academic Validation
  3. Generation of a Selective Small Molecule Inhibitor of the CBP/p300 Bromodomain for Leukemia Therapy

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

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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