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- W4285796615 abstract "Recent evidence suggests that deletion of STUB1─a pivotal negative regulator of interferon-γ sensing─may potentially clear malignant cells. However, current studies rely primarily on genetic approaches, as pharmacological inhibitors of STUB1 are lacking. Identifying a tool compound will be a step toward validating the target in a broader therapeutic sense. Herein, screening more than a billion macrocyclic peptides resulted in STUB1 binders, which were further optimized by a structure-enabled in silico design. The strategy to replace the macrocyclic peptides' hydrophilic and solvent-exposed region with a hydrophobic scaffold improved cellular permeability while maintaining the binding conformation. Further substitution of the permeability-limiting terminal aspartic acid with a tetrazole bioisostere retained the binding to a certain extent while improving permeability, suggesting a path forward. Although not optimal for cellular study, the current lead provides a valuable template for further development into selective tool compounds for STUB1 to enable target validation." @default.
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- W4285796615 date "2022-07-19" @default.
- W4285796615 modified "2023-10-17" @default.
- W4285796615 title "Discovery and Structure-Based Design of Macrocyclic Peptides Targeting STUB1" @default.
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- W4285796615 doi "https://doi.org/10.1021/acs.jmedchem.2c00406" @default.
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