title: Targeting acute myeloid leukemia with a small molecule inhibitor of the Myb/p300 interaction.
abstract: The transcription factor Myb plays a key role in the hematopoietic system and has been implicated in the development of leukemia and other human cancers. Inhibition of Myb is therefore emerging as a potential therapeutic strategy for these diseases. However, because of a lack of suitable inhibitors, the feasibility of therapeutic approaches based on Myb inhibition has not been explored. We have identified the triterpenoid Celastrol as a potent low-molecular-weight inhibitor of the interaction of Myb with its cooperation partner p300. We demonstrate that Celastrol suppresses the proliferative potential of acute myeloid leukemia (AML) cells while not affecting normal hematopoietic progenitor cells. Furthermore, Celastrol prolongs the survival of mice in a model of an aggressive AML. Overall, our work demonstrates the therapeutic potential of a small molecule inhibitor of the Myb/p300 interaction for the treatment of AML and provides a starting point for the further development of Myb-inhibitory compounds for the treatment of leukemia and, possibly, other tumors driven by deregulated Myb.
authors.affiliation: Institute for Biochemistry and Graduate School of Chemistry, University of Münster, Münster, Germany;
authors.forename: Sagar
authors.initials: S
authors.lastname: Uttarkar
authors.affiliation: Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom;
authors.forename: Emilie
authors.initials: E
authors.lastname: Dassé
authors.affiliation: Institute for Biochemistry and.
authors.forename: Anna
authors.initials: A
authors.lastname: Coulibaly
authors.affiliation: Institute for Biochemistry and.
authors.forename: Simone
authors.initials: S
authors.lastname: Steinmann
authors.affiliation: Institute for Biochemistry and.
authors.forename: Anke
authors.initials: A
authors.lastname: Jakobs
authors.affiliation: Institute for Pharmaceutical Biology and Phytochemistry and.
authors.forename: Caroline
authors.initials: C
authors.lastname: Schomburg
authors.affiliation: Institute for Biochemistry and.
authors.forename: Amke
authors.initials: A
authors.lastname: Trentmann
authors.affiliation: Institute for Pharmaceutical and Medicinal Chemistry, University of Münster, Münster, Germany;
authors.forename: Joachim
authors.initials: J
authors.lastname: Jose
authors.affiliation: Institute for Transfusion Medicine, University Hospital, University of Graz, Graz, Austria;
authors.forename: Peter
authors.initials: P
authors.lastname: Schlenke
authors.affiliation: Department of Medicine A, Hematology and Oncology, University Hospital, University of Münster, Münster, Germany; and.
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Berdel
authors.affiliation: Institute for Pharmaceutical Biology and Phytochemistry and.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Schmidt
authors.affiliation: Department of Medicine, Hematology and Oncology, University of Halle, Halle, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Müller-Tidow
authors.affiliation: Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom;
authors.forename: Jon
authors.initials: J
authors.lastname: Frampton
authors.affiliation: Institute for Biochemistry and.
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Klempnauer
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002645:Chickens; D004195:Disease Models, Animal; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D018922:HL-60 Cells; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D022423:Myeloid Cells / Q000187:drug effects / Q000473:pathology; D053978:Pentacyclic Triterpenes; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D020598:Proto-Oncogene Proteins c-myb / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000494:pharmacology / Q000627:therapeutic use*; D014315:Triterpenes / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D053978:Pentacyclic Triterpenes; D020598:Proto-Oncogene Proteins c-myb; D054852:Small Molecule Libraries; D014315:Triterpenes; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; C050414:celastrol