title: 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.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, Structural Genomics Consortium, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.|Nuffield Department of Clinical Medicine, University of Oxford, Ludwig Institute for Cancer Research (LICR), Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Picaud
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, Structural Genomics Consortium, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.|Nuffield Department of Clinical Medicine, University of Oxford, Target Discovery Institute (TDI), Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Oleg
authors.initials: O
authors.lastname: Fedorov
authors.affiliation: Laboratory of Childhood Leukemia, Department of Biomedicine, University of Basel and Basel University Children's Hospital, Hebelstrasse 20 CH - 4031 Basel, Switzerland.
authors.forename: Angeliki
authors.initials: A
authors.lastname: Thanasopoulou
authors.affiliation: Laboratory of Childhood Leukemia, Department of Biomedicine, University of Basel and Basel University Children's Hospital, Hebelstrasse 20 CH - 4031 Basel, Switzerland.
authors.forename: Katharina
authors.initials: K
authors.lastname: Leonards
authors.affiliation: Epinova DPU, Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage SG1 2NY, UK.
authors.forename: Katherine
authors.initials: K
authors.lastname: Jones
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, Structural Genomics Consortium, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.|Nuffield Department of Clinical Medicine, University of Oxford, Target Discovery Institute (TDI), Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Julia
authors.initials: J
authors.lastname: Meier
authors.affiliation: Laboratory of Cancer Biology, Department of Oncology, Medical Sciences Division, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK.
authors.forename: Heidi
authors.initials: H
authors.lastname: Olzscha
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, Structural Genomics Consortium, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.|Nuffield Department of Clinical Medicine, University of Oxford, Target Discovery Institute (TDI), Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Octovia
authors.initials: O
authors.lastname: Monteiro
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, Structural Genomics Consortium, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.|Nuffield Department of Clinical Medicine, University of Oxford, Target Discovery Institute (TDI), Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Martin
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, Structural Genomics Consortium, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.|Nuffield Department of Clinical Medicine, University of Oxford, Target Discovery Institute (TDI), Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Philpott
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, Structural Genomics Consortium, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.|Nuffield Department of Clinical Medicine, University of Oxford, Target Discovery Institute (TDI), Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Tumber
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, Structural Genomics Consortium, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.|Nuffield Department of Clinical Medicine, University of Oxford, Ludwig Institute for Cancer Research (LICR), Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Panagis
authors.initials: P
authors.lastname: Filippakopoulos
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, Target Discovery Institute (TDI), Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Clarence
authors.initials: C
authors.lastname: Yapp
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, Structural Genomics Consortium, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.|Nuffield Department of Clinical Medicine, University of Oxford, Target Discovery Institute (TDI), Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Wells
authors.affiliation: Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge CB2 1QN, UK.
authors.forename: Ka Hing
authors.initials: KH
authors.lastname: Che
authors.affiliation: Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge CB2 1QN, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Bannister
authors.affiliation: Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge CB2 1QN, UK.
authors.forename: Samuel
authors.initials: S
authors.lastname: Robson
authors.affiliation: Epinova DPU, Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage SG1 2NY, UK.
authors.forename: Umesh
authors.initials: U
authors.lastname: Kumar
authors.affiliation: Epinova DPU, Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage SG1 2NY, UK.
authors.forename: Nigel
authors.initials: N
authors.lastname: Parr
authors.affiliation: Epinova DPU, Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage SG1 2NY, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Lee
authors.affiliation: Experimental Medicines Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, UK.
authors.forename: Dave
authors.initials: D
authors.lastname: Lugo
authors.affiliation: Experimental Medicines Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Jeffrey
authors.affiliation: Experimental Medicines Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Taylor
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, Target Discovery Institute (TDI), Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Matteo L
authors.initials: ML
authors.lastname: Vecellio
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, Structural Genomics Consortium, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Chas
authors.initials: C
authors.lastname: Bountra
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, Structural Genomics Consortium, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.|Nuffield Department of Clinical Medicine, University of Oxford, Target Discovery Institute (TDI), Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Brennan
authors.affiliation: BioSeek Division of DiscoveRx Corporation, 310 Utah Street, Suite 100, South San Francisco, CA, 94080, USA.
authors.forename: Alison
authors.initials: A
authors.lastname: O'Mahony
authors.affiliation: BioSeek Division of DiscoveRx Corporation, 310 Utah Street, Suite 100, South San Francisco, CA, 94080, USA.
authors.forename: Sharlene
authors.initials: S
authors.lastname: Velichko
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, Structural Genomics Consortium, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.|Nuffield Department of Clinical Medicine, University of Oxford, Target Discovery Institute (TDI), Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Susanne
authors.initials: S
authors.lastname: Müller
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, Target Discovery Institute (TDI), Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Duncan
authors.initials: D
authors.lastname: Hay
authors.affiliation: Promega Corporation, 2800 Woods Hollow Road, Madison, Wisconsin, U.S.A 53711.
authors.forename: Danette L
authors.initials: DL
authors.lastname: Daniels
authors.affiliation: Promega Corporation, 2800 Woods Hollow Road, Madison, Wisconsin, U.S.A 53711.
authors.forename: Marjeta
authors.initials: M
authors.lastname: Urh
authors.affiliation: Laboratory of Cancer Biology, Department of Oncology, Medical Sciences Division, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK.
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: La Thangue
authors.affiliation: Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge CB2 1QN, UK.
authors.forename: Tony
authors.initials: T
authors.lastname: Kouzarides
authors.affiliation: Epinova DPU, Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage SG1 2NY, UK.
authors.forename: Rab
authors.initials: R
authors.lastname: Prinjha
authors.affiliation: Laboratory of Childhood Leukemia, Department of Biomedicine, University of Basel and Basel University Children's Hospital, Hebelstrasse 20 CH - 4031 Basel, Switzerland.
authors.forename: Jürg
authors.initials: J
authors.lastname: Schwaller
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, Structural Genomics Consortium, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.|Nuffield Department of Clinical Medicine, University of Oxford, Target Discovery Institute (TDI), Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010077:Oxazepines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D023041:Xenograft Model Antitumor Assays; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D010077:Oxazepines; D004317:Doxorubicin; D050880:p300-CBP Transcription Factors