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Computational approach to target USP28 for regulating Myc
Debangana Chakravorty1, Abhirupa Ghosh1, Sudipto Saha1
1Division of Bioinformatics, Bose Institute, Kolkata, India.
Abstract:
Myc is a crucial player in cellular proliferation and a known regulator of cancer pathobiology. Modulation of Myc expression targeting the Myc Protein-Protein Interactors (PPIs) like Myc-Max has till now been the most explored approach. However, this approach threatens the normal cells where Myc expression is required for proliferation. This demands the need for a new strategy to indirectly modulate Myc expression. Indirect modulation can be achieved by regulating Myc turnover. FBXW7 mediates the ubiquitination and subsequent degradation of Myc which is reversed by USP28. In this study, the interaction of USP28 with FBXW7 as well as with its substrate, Ubiquitin (Ub) were used as targets. Computation based high-throughput screening of bioactive small chemicals using molecular docking method was implemented to predict USP28 inhibitors. For the two regions, docking study with AutoDock Vina gave top 10 best scoring drugs which were identified and tabulated. The two regions defined in the study as FBXW7 binding and Ub binding also encompass the areas in which USP28 differed from USP25, a homologue with a different role. Out of these the best scoring drugs were explored for their role in cancer, if any. This study was performed keeping in mind re-purposing of these known drugs for possible alternative anti-Myc cancer therapy.
Insights
This study identifies novel small molecule inhibitors targeting USP28 to indirectly modulate Myc expression, offering a potential new strategy for anti-cancer therapy by repurposing existing drugs.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Myc is essential for cell proliferation and cancer development.
- Targeting Myc directly has limitations due to its role in normal cell function.
- Modulating Myc turnover offers an alternative therapeutic strategy.
Purpose of the Study:
- To identify small molecules that inhibit USP28, a key regulator of Myc degradation.
- To explore drug repurposing for novel anti-Myc cancer therapies.
- To investigate USP28 as a therapeutic target by analyzing its interactions with FBXW7 and Ubiquitin.
Main Methods:
- Computational high-throughput screening using molecular docking (AutoDock Vina).
- Identification of potential USP28 inhibitors by screening bioactive small chemicals.
- Analysis of USP28 binding sites (FBXW7 and Ubiquitin) and comparison with USP25.
Main Results:
- Top 10 drug candidates predicted to inhibit USP28 binding to FBXW7 and Ubiquitin.
- Identified specific binding regions on USP28 that differ from its homolog USP25.
- Explored the anti-cancer potential of the top-scoring drug candidates.
Conclusions:
- USP28 inhibition represents a promising indirect strategy for modulating Myc in cancer therapy.
- Drug repurposing of identified inhibitors could lead to novel anti-Myc treatments.
- This study provides a foundation for developing new anti-cancer drugs targeting Myc regulation.
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