title: CBP/catenin antagonist safely eliminates drug-resistant leukemia-initiating cells.
abstract: CREB-binding protein (CBP) and p300 are highly homologous transcriptional coactivators with unique, non-redundant roles that bind a wide array of proteins, including catenins-β and γ. ICG-001 is a small-molecule inhibitor that specifically inhibits the CBP/catenin interaction. Importantly, ICG-001 does not inhibit the p300/catenin interaction. We demonstrate that specifically inhibiting the interaction between CBP and catenin with ICG-001 results in the differentiation of quiescent drug-resistant chronic myelogenous leukemia-initiating cells (CML LICs), thereby sensitizing them to BCR-ABL tyrosine kinase inhibitors, for example, Imatinib. Using ICG-001 in a NOD/SCID/IL2Rγ(-/-) mouse model of engrafted human chronic myelogenous leukemia, we now demonstrate the complete elimination of engrafted leukemia after only one course of combined chemotherapy. Combination-treated animals live as long as their non-engrafted littermates. Results from these studies demonstrate that specifically antagonizing the CBP/catenin interaction with ICG-001 can eliminate drug-resistant CML LICs without deleterious effects to the normal endogenous hematopoietic stem cell population.
authors.affiliation: Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.|Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.|Center for Molecular Pathways and Drug Discovery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Center for Molecular Pathways and Drug Discovery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Masiello
authors.affiliation: Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.|Center for Molecular Pathways and Drug Discovery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: McMillian
authors.affiliation: Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.|Center for Molecular Pathways and Drug Discovery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Nguyen
authors.affiliation: Center for Molecular Pathways and Drug Discovery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.|Center for Molecular Pathways and Drug Discovery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Melendez
authors.affiliation: Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.|Center for Molecular Pathways and Drug Discovery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Smbatyan
authors.affiliation: Center for Molecular Pathways and Drug Discovery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Kida
authors.affiliation: Center for Molecular Pathways and Drug Discovery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: He
authors.affiliation: Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.|Center for Molecular Pathways and Drug Discovery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: J-L
authors.initials: JL
authors.lastname: Teo
authors.affiliation: Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.|Center for Molecular Pathways and Drug Discovery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.|Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.|Department of Molecular Pharmacology and Toxicology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kahn
mesh_terms: D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D050882:CREB-Binding Protein / Q000378:metabolism*; D051177:Catenins / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011744:Pyrimidinones / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D051177:Catenins; C492448:ICG 001; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D011744:Pyrimidinones; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D016044:Fusion Proteins, bcr-abl