Decoding MYC Targeted Inhibition in Cancer: Integrating Medicinal Insights With Computational Design Approaches
Subhankar Pradhan1, Shivani Kasana1, Balak Das Kurmi2
1Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, Punjab, India.
Abstract:
The MYC family of oncoproteins, a central regulator of cellular proliferation and metabolism, is aberrantly regulated in over 70% of human cancers, making them a significant target for therapeutic intervention. Yet, MYC intrinsically disordered conformation and exclusive nuclear localisation have led to its popularity as 'undruggable'. This review provides an in-depth evaluation of the structure-activity relationship (SAR) of diverse small-molecule inhibitors designed to target the undruggable MYC. We highlighted a spectrum of chemical scaffolds, including indenoisoquinoline, dibenzoquinoxaline, isaindigotone, quindoline, berberine and iminobenzimidazole derivatives and many others. The described inhibitors act by two primary mechanisms: disrupting the essential MYC-MAX dimerisation and stabilising the c-Myc promoter G-quadruplex (G4) to suppress MYC transcription. Key SAR insights highlight the critical contributions in distinct structural motifs, including planar aromatic cores for π-π stacking, cationic side chains for electrostatic interactions and precisely positioned electron-donating or electron-withdrawing groups that determine inhibitory potency and selectivity. In silico docking studies highlighted the key interactions of the corresponding ligand molecules with the amino acid residues present within the active pocket of the MYC target. By systematically correlating chemical structure with biological activity across multiple classes through SAR and computational studies, this review establishes a robust framework to guide the rational development of next-generation MYC inhibitors with enhanced clinical potential.
Insights
Researchers reviewed small-molecule inhibitors targeting the MYC oncoprotein, often considered "undruggable." They analyzed structure-activity relationships to guide the development of new MYC-targeted cancer therapies.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- The MYC oncoprotein family regulates cell proliferation and metabolism, and is dysregulated in over 70% of human cancers.
- MYC's disordered structure and nuclear localization present challenges, earning it the 'undruggable' moniker.
- Targeting MYC is crucial for cancer therapeutic intervention.
Purpose of the Study:
- To evaluate the structure-activity relationship (SAR) of small-molecule inhibitors targeting MYC.
- To provide a framework for developing next-generation MYC inhibitors with improved clinical potential.
Main Methods:
- Review of diverse chemical scaffolds targeting MYC, including indenoisoquinoline, dibenzoquinoxaline, and others.
- Analysis of two primary inhibition mechanisms: disruption of MYC-MAX dimerization and stabilization of the c-Myc promoter G-quadruplex (G4).
- In silico docking studies to identify key ligand-protein interactions within the MYC active pocket.
Main Results:
- Identified key structural motifs contributing to MYC inhibitor potency and selectivity, such as planar aromatic cores and cationic side chains.
- Highlighted specific interactions between inhibitor molecules and MYC active site residues.
- Correlated chemical structure with biological activity across multiple inhibitor classes.
Conclusions:
- Established a robust framework for rational drug design of MYC inhibitors based on SAR and computational studies.
- Demonstrated the potential for developing effective MYC-targeted therapies despite previous challenges.
- Advanced the understanding of how small molecules can effectively target the MYC oncoprotein.
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