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Updated: Sep 27, 2025
Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
Published on: October 23, 2019
Src-Family Protein Kinase Inhibitors Suppress MYB Activity in a p300-Dependent Manner
Abhiruchi Biyanee1, Maria V Yusenko1, Karl-Heinz Klempnauer1
1Institute for Biochemistry, Westfälische-Wilhelms-Universität, D-48149 Münster, Germany.
Abstract:
Recent studies have disclosed transcription factor MYB as a potential drug target for malignancies that are dependent on deregulated MYB function, including acute myeloid leukemia (AML) and adenoid cystic carcinoma (ACC). Although transcription factors are often regarded as undruggable, successful targeting of MYB by low-molecular-weight compounds has recently been demonstrated. In an attempt to repurpose known drugs as novel MYB-inhibitory agents, we have screened libraries of approved drugs and drug-like compounds for molecules with MYB-inhibitory potential. Here, we present initial evidence for the MYB-inhibitory activity of the protein kinase inhibitors bosutinib, PD180970 and PD161570, that we identified in a recent screen. We show that these compounds interfere with the activity of the MYB transactivation domain, apparently by disturbing the ability of MYB to cooperate with the coactivator p300. We show that treatment of the AML cell line HL60 with these compounds triggers the up-regulation of the myeloid differentiation marker CD11b and induces cell death. Importantly, we show that these effects are significantly dampened by forced expression of an activated version of MYB, confirming that the ability to suppress MYB function is a relevant activity of these compounds. Overall, our work identifies several protein kinase inhibitors as novel MYB-inhibitory agents and suggests that the inhibition of MYB function may play a role in their pharmacological impact on leukemic cells.
Insights
Protein kinase inhibitors bosutinib, PD180970, and PD161570 show MYB inhibitory activity. These drugs may offer new treatments for acute myeloid leukemia (AML) by targeting MYB function.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Transcription factor MYB is a key driver in malignancies like acute myeloid leukemia (AML).
- Targeting transcription factors like MYB has been challenging, but recent successes with small molecules are promising.
- Repurposing existing drugs offers a faster route to novel cancer therapies.
Purpose of the Study:
- To identify existing drugs with MYB-inhibitory potential for cancer treatment.
- To investigate the mechanism of MYB inhibition by identified compounds.
- To evaluate the therapeutic effects of MYB inhibitors in AML models.
Main Methods:
- Screening of approved drugs and drug-like compounds for MYB inhibitory activity.
- Assessing the impact of compounds on MYB transactivation domain and p300 coactivator interaction.
- Treating acute myeloid leukemia (AML) cell line HL60 with identified compounds.
- Analyzing myeloid differentiation marker CD11b expression and cell death induction.
- Validating MYB inhibition relevance using forced expression of activated MYB.
Main Results:
- Identified bosutinib, PD180970, and PD161570 as MYB-inhibitory agents.
- Demonstrated that these compounds disrupt MYB cooperation with the p300 coactivator.
- Observed induction of CD11b expression and cell death in HL60 cells.
- Confirmed that MYB inhibition is responsible for the observed anti-leukemic effects.
Conclusions:
- Protein kinase inhibitors bosutinib, PD180970, and PD161570 are novel MYB inhibitors.
- MYB inhibition by these compounds has a relevant pharmacological impact on leukemic cells.
- These findings suggest a potential therapeutic strategy for MYB-dependent cancers.
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