Unifying Catalysis Framework to Dissect Proteasomal Degradation Paradigms
Year: 2021
Type: review
Abstract: Diverging from traditional target inhibition, proteasomal protein degradation approaches have emerged as novel therapeutic modalities that embody distinct pharmacological profiles and can access previously undrugged targets. Small molecule degraders have the potential to catalytically destroy target proteins at substoichiometric concentrations, thus lowering administered doses and extending pharmacological effects. With this mechanistic premise, research efforts have advanced the development of small molecule degraders that benefit from stable and increased affinity ternary complexes. However, a holistic framework that evaluates different degradation modes from a catalytic perspective, including focusing on kinetically favored degradation mechanisms, is lacking. In this Outlook, we introduce the concept of an induced cooperativity spectrum as a unifying framework to mechanistically understand catalytic degradation profiles. This framework is bolstered by key examples of published molecular degraders extending from molecular glues to bivalent degraders. Critically, we discuss remaining challenges and future opportunities in drug discovery to rationally design and phenotypically screen for efficient degraders.
Source: ACS Central Science
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: diamond
OpenAlex ID: W3167795530