Small-Molecule Hydrophobic Tagging: A Promising Strategy of Druglike Technology for Targeted Protein Degradation

Abstract

BiographiesShaowen Xie received his B.S. degree in pharmacy from China Pharmaceutical University in 2017. Currently, he is a doctoral candidate in the field of medicinal chemistry at China Pharmaceutical University. His research primarily focuses on the development and mechanism investigation of small molecule degraders targeting specific proteins.

Recent advances in the understanding of cilia mechanisms and their applications as therapeutic targets

“…In silico approach using the International Mouse Phenotype Consortium data and STRING, a database of known and predicted protein-protein interactions, have successfully found novel ciliopathy genes ( Higgins et al, 2022 ). Chemicals to regulate these ciliary genes could be generated using technologies that lead to targeted protein degradation, such as proteolysis-targeting chimeras and small-molecule hydrophobic tagging ( Bhole et al, 2023 ; Xie et al, 2023 ). In vitro phenotypic screening can also be used for repositioning clinical drugs to treat ciliopathies ( Benmerah et al, 2023 ).…”

Recent Discovery and Development of Inhibitors that Target CDK9 and Their Therapeutic Indications

“…90 degrades CDK9 through the autophagy–lysosome strategy, presenting a novel intracellular protein degradation method that broadens the scope of protein degradation, including CDK9. The HyT technique relies on compounds containing a ligand for the target protein and a large hydrophobic moiety to increase the hydrophobicity of the target protein’s surface, inducing protein instability and misfolding, ultimately leading to its degradation by the proteasome . LL-K9-03-SNS032 ( 91 ) is a novel inhibitor, applying this approach.…”

Targeted Protein Degradation of Histone Deacetylases by Hydrophobically Tagged Inhibitors

“…In the case of hydrophobic tagging, refolding fails and degradation occurs . Another proposed mechanism of hydrophobic tagging suggests that the binding of a hydrophobically tagged ligand results in the destabilization of the target protein, subsequently facilitating its degradation by the proteasome . In this scenario, a target protein with greater stability would be less vulnerable to hydrophobic tagging .…”

“…Another proposed mechanism of hydrophobic tagging suggests that the binding of a hydrophobically tagged ligand results in the destabilization of the target protein, subsequently facilitating its degradation by the proteasome . In this scenario, a target protein with greater stability would be less vulnerable to hydrophobic tagging . In general, our understanding of the degradation mechanism involving HyT’s is still in its early stages, making it challenging to predict whether a specific POI can be effectively degraded using the hydrophobic tagging approach .…”

“…In this scenario, a target protein with greater stability would be less vulnerable to hydrophobic tagging . In general, our understanding of the degradation mechanism involving HyT’s is still in its early stages, making it challenging to predict whether a specific POI can be effectively degraded using the hydrophobic tagging approach . The first HyT’s utilized the Halo-Tag ligand to degrade transmembrane proteins as well as the tumor target Hras1 G12V .…”