蛋白酶体
细胞生物学
泛素
化学生物学
计算机科学
生物
泛素连接酶
降级(电信)
作者
Frances P. Rodriguez-Rivera,Samuel M. Levi
出处
期刊:ACS central science
[American Chemical Society]
日期:2021-07-28
卷期号:7 (7): 1117-1125
被引量:2
标识
DOI:10.1021/acscentsci.1c00389
摘要
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.
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