Inducing Protein Degradation to Overcome Resistance to Kinase Inhibitors

Sato, Waka; Naito, Mikihiko

doi:10.1021/acs.biochem.2c00223

Cited by 1 publication

(2 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This lowers the bar with respect to the affinity and half-life of the TP–ligand complex required for suppression of its activity relative to traditional occupancy-driven inhibitors. Second, PROTACs need not bind to the active site of the TP, with potential for the selective degradation of particular members of protein families with highly homologous active sites, such as kinases. , …”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Reversible Assembly of Proteolysis Targeting Chimeras

et al. 2023

View full text Add to dashboard Cite

PROteolysis TArgeting Chimeras (PROTACs) are of significant current interest for the development of probe molecules and drug leads. However, they suffer from certain limitations. PROTACs are rule-breaking molecules with sub-optimal cellular permeability, solubility, and other drug-like properties. In particular, they exhibit an unusual dose−response curve where high concentrations of the bivalent molecule inhibit degradation activity, a phenomenon known as the hook effect. This will likely complicate their use in vivo. In this study, we explore a novel approach to create PROTACs that do not exhibit a hook effect. This is achieved by equipping the target protein and E3 ubiquitin ligase ligands with functionalities that undergo rapid and reversible covalent assembly in cellulo. We report the development of Self-Assembled Proteolysis Targeting Chimeras that mediate the degradation of the Von Hippel−Lindau E3 ubiquitin ligase and do not evince a hook effect.

show abstract

Section: Introductionmentioning

confidence: 99%

“…Second, PROTACs need not bind to the active site of the TP, with potential for the selective degradation of particular members of protein families with highly homologous active sites, such as kinases. 10,11 However, PROTACs have some drawbacks. Most are rulebreaking molecules with respect to traditional medicinal chemistry guidelines.…”

Section: ■ Introductionmentioning

confidence: 99%