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Discovery and Structure-Based Design of Macrocyclic Peptides Targeting STUB1
Simon Ng1, Alexander C Brueckner2, Soheila Bahmanjah2
1Quantitative Biosciences, MSD, 8 Biomedical Grove, Singapore 138665.
Journal of Medicinal Chemistry
|July 19, 2022
Summary
Researchers identified novel STUB1 binders, a key regulator in cancer, using macrocyclic peptides and computational design. This work offers a foundation for developing STUB1 inhibitors for cancer therapy.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- STUB1 is a negative regulator of interferon-gamma sensing and its deletion may clear malignant cells.
- Genetic approaches are primary for STUB1 studies, but pharmacological inhibitors are lacking.
- A tool compound is needed to validate STUB1 as a therapeutic target.
Purpose of the Study:
- To identify and optimize STUB1 binders as potential pharmacological tools.
- To develop a chemical strategy for improving cellular permeability of STUB1 inhibitors.
Main Methods:
- Screening of over a billion macrocyclic peptides for STUB1 binding.
- Structure-enabled in silico design for optimization.
- Modification of peptide scaffolds to enhance cellular permeability.
Main Results:
- Identification of STUB1-binding macrocyclic peptides.
- Optimization using in silico design improved cellular permeability.
- Substitution with a tetrazole bioisostere maintained binding while enhancing permeability.
Conclusions:
- The developed lead compound serves as a template for selective STUB1 tool compounds.
- Further development is needed for optimal cellular studies and target validation.
- This research provides a pathway toward pharmacological targeting of STUB1 in cancer.
