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

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.

• Authors: Sarah Picaud, Oleg Fedorov, Angeliki Thanasopoulou, Katharina Leonards, Katherine Jones, Julia Meier, Heidi Olzscha, Octovia Monteiro, Sarah Martin, Martin Philpott, Anthony Tumber, Panagis Filippakopoulos, Clarence Yapp, Christopher Wells, Ka Hing Che, Andrew Bannister, Samuel Robson, Umesh Kumar, Nigel Parr, Kevin Lee, Dave Lugo, Philip Jeffrey, Simon Taylor, Matteo L Vecellio, Chas Bountra, Paul E Brennan, Alison O'Mahony, Sharlene Velichko, Susanne Müller, Duncan Hay, Danette L Daniels, Marjeta Urh, Nicholas B La Thangue, Tony Kouzarides, Rab Prinjha, Jürg Schwaller, Stefan Knapp
• Journal: Cancer research (Cancer Res) Vol. 75 Issue 23 Pg. 5106-5119 (Dec 01 2015) ISSN: 1538-7445 [Electronic] United States
• PMID: 26552700 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Enzyme Inhibitors
• Oxazepines
• Doxorubicin
• p300-CBP Transcription Factors

Topics

• Amino Acid Sequence
• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Cell Line, Tumor
• Doxorubicin (administration & dosage, pharmacology)
• Drug Synergism
• Enzyme Inhibitors (administration & dosage, chemistry, pharmacology)
• Humans
• Leukemia, Myeloid, Acute (drug therapy, enzymology)
• Mice
• Models, Molecular
• Molecular Sequence Data
• Oxazepines (administration & dosage, chemistry, pharmacology)
• Protein Structure, Tertiary
• Xenograft Model Antitumor Assays
• p300-CBP Transcription Factors (antagonists & inhibitors, chemistry)