Naphthol AS-E Phosphate Inhibits the Activity of the Transcription Factor Myb by Blocking the Interaction with the KIX Domain of the Coactivator p300.
The transcription factor c-Myb is highly expressed in hematopoietic progenitor cells and controls the transcription of genes important for lineage determination, cell proliferation, and differentiation. Deregulation of c-Myb has been implicated in the development of leukemia and certain other types of human cancer. c-Myb activity is highly dependent on the interaction of the c-Myb with the KIX domain of the coactivator p300, making the disruption of this interaction a reasonable strategy for the development of Myb inhibitors. Here, we have used bacterial Autodisplay to develop an in vitro binding assay that mimics the interaction of Myb and the KIX domain of p300. We have used this binding assay to investigate the potential of Naphthol AS-E phosphate, a compound known to bind to the KIX domain, to disrupt the interaction between Myb and p300. Our data show that Naphthol AS-E phosphate interferes with the Myb-KIX interaction in vitro and inhibits Myb activity in vivo. By using several human leukemia cell lines, we demonstrate that Naphthol AS-E phosphate suppresses the expression of Myb target genes and induces myeloid differentiation and apoptosis. Our work identifies Naphthol AS-E phosphate as the first low molecular weight compound that inhibits Myb activity by disrupting its interaction with p300, and suggests that inhibition of the Myb-KIX interaction might be a useful strategy for the treatment of leukemia and other tumors caused by deregulated c-Myb.
Institute for Biochemistry, Westfälische-Wilhelms-Universität Münster, Münster, Germany. Graduate School of Chemistry (GSC-MS), Westfälische-Wilhelms-Universität Münster, Münster, Germany.
Sagar
S
Uttarkar
Institute for Biochemistry, Westfälische-Wilhelms-Universität Münster, Münster, Germany. Graduate School of Chemistry (GSC-MS), Westfälische-Wilhelms-Universität Münster, Münster, Germany.
Sandeep
S
Dukare
Institute for Pharmaceutical and Medicinal Chemistry, Westfälische-Wilhelms-Universität Münster, Münster, Germany.
Bertan
B
Bopp
Institute for Pharmaceutical and Medicinal Chemistry, Westfälische-Wilhelms-Universität Münster, Münster, Germany.
Michael
M
Goblirsch
Institute for Pharmaceutical and Medicinal Chemistry, Westfälische-Wilhelms-Universität Münster, Münster, Germany.
Joachim
J
Jose
Institute for Biochemistry, Westfälische-Wilhelms-Universität Münster, Münster, Germany. klempna@uni-muenster.de.
Karl-Heinz
KH
Klempnauer
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics; D018922:HL-60 Cells; D006801:Humans; D008856:Microscopy, Fluorescence; D009284:Naphthols / Q000378:metabolism / Q000494:pharmacology*; D010755:Organophosphates / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D020598:Proto-Oncogene Proteins c-myb / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020298:U937 Cells
D009284:Naphthols; D010755:Organophosphates; D020598:Proto-Oncogene Proteins c-myb; C495860:naphthol AS-E phosphate; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human