MYB Inhibitors Disrupt Protein Complexes to Reduce Leukemia Levels
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Solution Overview
Problem
The MYB protein is difficult to target using small molecule probes due to its disordered conformational structure, making it challenging to selectively inhibit MYB function in leukemic cells while sparing normal hematopoiesis.
Innovation Solution
Development of new compounds of Formula (I) and their pharmaceutical compositions that inhibit MYB function by contacting the MYB protein or its associated proteins, thereby reducing MYB protein levels in cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If small molecule probes are used to target MYB protein, then the difficulty of targeting increases due to disordered conformational structure, but selective inhibition of MYB function in leukemic cells is required
Solution Approach 1:
The patent uses an MYB complex partner as an intermediary to indirectly inhibit MYB function. Instead of directly targeting the difficult-to-access MYB protein, the compounds bind to MYB's interaction partners (such as TAF12, TAF1, or TAF2), disrupting the MYB complex formation and thereby inhibiting MYB's transcriptional activity in leukemic cells
Solution Approach 2:
The patent replaces direct physical binding to MYB with a biochemical mechanism of disrupting protein-protein interactions. By targeting the interaction interface between MYB and its partners, the compounds achieve functional inhibition through biochemical disruption rather than direct mechanical binding to MYB's disordered structure
Data Source
AI summary
Provided herein are compounds that inhibit the function of MYB. In particular, provided are compounds that can inhibit MYB and/or disrupt the interaction between MYB and a protein associated with MYB, a protein whose dysregulation is implicated in cancer. Also provided are pharmaceutical compositions comprising the compounds, methods of inhibiting MYB function, and methods of treating cancer in a subject by administering a compound or composition described herein.