Naphthol AS-E Phosphate Inhibits the Activity of the Transcription Factor Myb by Blocking the Interaction with the KIX Domain of the Coactivator p300

Uttarkar, Sagar; Dukare, Sandeep; Bopp, Bertan; Goblirsch, Michael; Jose, Joachim; Klempnauer, Karl‐Heinz

doi:10.1158/1535-7163.mct-14-0662

Cited by 62 publications

(67 citation statements)

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“…We have recently identified another compound, Naphthol AS-E phosphate, which inhibits Myb activity in a similar manner, underscoring the "druggability" of the Myb-KIX protein-protein interaction. 46 Our data show that Celastrol inhibits the expression of bona fide Myb-regulated genes and, depending on its concentration, induces differentiation or apoptosis of HL60 cells. Interestingly, the differentiation-inducing activity of Celastrol was further increased by other compounds, such as ATRA or the broad-spectrum histone deacetylase inhibitor LBH589, which synergistically induced differentiation of HL60 cells in combination with Celastrol.…”

Section: Discussionmentioning

confidence: 62%

“…1,38,46,60 Most acute myeloid and lymphoid leukemia cells express high levels of Myb and are more dependent on, or addicted to, Myb expression than normal hematopoietic progenitor cells. 28 This has raised the possibility that inhibitors of Myb might be able to eradicate the leukemic cells while leaving normal hematopoietic progenitors unaffected.…”

Section: Discussionmentioning

confidence: 99%

“…46 Bacterial autodisplay provides a powerful experimental platform for the analysis of protein-protein interactions and the development of inhibitors.…”

Section: Celastrol Disrupts the Myb-p300 Interactionmentioning

confidence: 99%

“…46 Bacterial autodisplay provides a powerful experimental platform for the analysis of protein-protein interactions and the development of inhibitors. 47,48 Figure 3B shows that bacteria, which express the KIX domain on their surface, were able to bind GFP-Myb but not GFP.…”

Section: Celastrol Disrupts the Myb-p300 Interactionmentioning

confidence: 99%

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Targeting acute myeloid leukemia with a small molecule inhibitor of the Myb/p300 interaction

Uttarkar

Dassé

Coulibaly³

et al. 2016

Blood

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129

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Key Points• Inhibition of Myb activity by a small molecule blocks proliferation of AML cells and prolongs survival of mice in an in vivo AML model.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. (Blood. 2016;127(9):1173-1182 Introduction Myb, the protein encoded by the MYB proto-oncogene, is now recognized as an attractive therapeutic target for the treatment of leukemia and potentially for other human tumors.1 Myb was originally discovered as the cellular progenitor of the transforming v-Myb transduced by avian myeloblastosis virus. 2,3 Myb is expressed in the hematopoietic progenitor cells, where it acts as a transcription factor to control genes important for lineage determination, cell proliferation, and differentiation. 4,5 The analysis of Myb null and conditional knockout mice and of mice bearing hypomorphic Myb alleles has demonstrated that Myb is essential for most hematopoietic lineages. [6][7][8][9][10][11] Myb is also expressed in several nonhematopoietic tissues, 12 such as the colonic crypts, where it controls the proliferation and differentiation of the intestinal stem cells. 13 Recent work has shown that deregulated Myb plays critical roles in leukemias and other types of cancer. Recurrent translocations and duplications of the Myb locus occur in acute lymphoblastic leukemia of young children. [14][15][16] In addition, genomic rearrangements of Myb have been reported in acute myelomonocytic and basophilic leukemia. [17][18][19] Although such rearrangements are relatively rare, they indicate that aberrant Myb expression contributes to the development of leukemia. Importantly, it has now been realized that Myb also plays essential roles in leukemias caused by genetic lesions of other genes, such as leukemias driven by human acute myeloid leukemia (AML) oncogenes. [20][21][22][23][24][25][26] High expression of Myb is a common characteristic of these leukemias and is essential for maintenance of the leukemic cells. This was initially observed in studies with Myb ant...

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Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

“…46 Bacterial autodisplay provides a powerful experimental platform for the analysis of protein-protein interactions and the development of inhibitors.…”

Section: Celastrol Disrupts the Myb-p300 Interactionmentioning

confidence: 99%

Section: Celastrol Disrupts the Myb-p300 Interactionmentioning

confidence: 99%

See 2 more Smart Citations

Targeting acute myeloid leukemia with a small molecule inhibitor of the Myb/p300 interaction

Uttarkar

Dassé

Coulibaly³

et al. 2016

Blood

Self Cite

129

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“…Naphthol AS-E phosphate blocks the interaction between MYB and CBP/P300 in vitro (Kasper et al, 2013, Uttarkar et al, 2015. This requires further in vivo and clinical studies.…”

Section: Final Conclusionmentioning

confidence: 98%

Understanding the role of the MYB oncogene in human breast cancer: targets and functions

Yang¹

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Dual Labeling of the CBP/p300 KIX Domain for ¹⁹F NMR Leads to Identification of a New Small‐Molecule Binding Site

et al. 2018

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Protein-Observed Fluorine NMR (PrOF NMR) spectroscopy is an emerging technique for screening and characterizing small-molecule-protein interactions. The choice of which amino acid to label for PrOF NMR can be critical for analysis. Here we report the first use of a protein containing two different fluoroaromatic amino acids for NMR studies. Using the KIX domain of the CBP/p300 as a model system, we examine ligand binding of several small-molecule compounds elaborated from our previous fragment screen and identify a new ligand binding site distinct from those used by native transcription factors. This site was further supported by computational modeling (FTMap and Schrödinger) and H, N HSQC/HMQC NMR spectroscopy. Metabolic labeling with multiple fluorinated amino acids provides useful probes for further studying ligand binding and has led to new insight for allosterically regulating transcription-factor protein interactions with small-molecule ligands.

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Naphthol AS-E Phosphate Inhibits the Activity of the Transcription Factor Myb by Blocking the Interaction with the KIX Domain of the Coactivator p300

Cited by 62 publications

References 47 publications

Targeting acute myeloid leukemia with a small molecule inhibitor of the Myb/p300 interaction

Targeting acute myeloid leukemia with a small molecule inhibitor of the Myb/p300 interaction

Understanding the role of the MYB oncogene in human breast cancer: targets and functions

Dual Labeling of the CBP/p300 KIX Domain for ¹⁹F NMR Leads to Identification of a New Small‐Molecule Binding Site

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Naphthol AS-E Phosphate Inhibits the Activity of the Transcription Factor Myb by Blocking the Interaction with the KIX Domain of the Coactivator p300

Cited by 62 publications

References 47 publications

Targeting acute myeloid leukemia with a small molecule inhibitor of the Myb/p300 interaction

Targeting acute myeloid leukemia with a small molecule inhibitor of the Myb/p300 interaction

Understanding the role of the MYB oncogene in human breast cancer: targets and functions

Dual Labeling of the CBP/p300 KIX Domain for 19F NMR Leads to Identification of a New Small‐Molecule Binding Site

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Dual Labeling of the CBP/p300 KIX Domain for ¹⁹F NMR Leads to Identification of a New Small‐Molecule Binding Site