Signal transducer and activator of transcription 3(STAT3)is a member of the transcription factors involved in regulating many physiological and pathological processes,such as cell proliferation,angiogenesis and immune...Signal transducer and activator of transcription 3(STAT3)is a member of the transcription factors involved in regulating many physiological and pathological processes,such as cell proliferation,angiogenesis and immune escape.STAT3 has been identified as a potential therapeutic target for various cancers.Although numerous STAT3 inhibitors have been discovered and optimized to directly inhibit STAT3 activity,they are not yet authorized for clinical use and only a few have entered clinical trials.Furthermore,several proteolysis-targeting chimera(PROTAC)molecules with STAT3 degrading effects have been developed.The event-driven action of PROTAC overcome the drawbacks of STAT3,a traditional undruggable target,and addressed possible resistance to small-molecule inhibitors by degrading the entire STAT3 protein.In this review,we presented a brief introduction to STAT3 and its functions in various cancers,and systematically overviewed the pharmacological effects of inhibitors targeting different domains of STAT3 in the last three years,the structural characterization of the main scaffold,the design strategies,and the pharmacological activities of the substituents.Also,the binding patterns and interactions of some inhibitors with STAT3 were analyzed in detail and the recent advances in STAT3 degraders are also summarized.We anticipate that this perspective will contribute to the design and optimize more novel effective and specific STAT3 inhibitors or degraders for carcinoma treatment.展开更多
基金supported by grants from the National Key Research and Development Program of China(No.2023YFA1800403)The Science and Technology Commission of Shanghai Municipality(No.21S11907800)Key Research and Development Program of Ningxia(No.2023BEG02010).
文摘Signal transducer and activator of transcription 3(STAT3)is a member of the transcription factors involved in regulating many physiological and pathological processes,such as cell proliferation,angiogenesis and immune escape.STAT3 has been identified as a potential therapeutic target for various cancers.Although numerous STAT3 inhibitors have been discovered and optimized to directly inhibit STAT3 activity,they are not yet authorized for clinical use and only a few have entered clinical trials.Furthermore,several proteolysis-targeting chimera(PROTAC)molecules with STAT3 degrading effects have been developed.The event-driven action of PROTAC overcome the drawbacks of STAT3,a traditional undruggable target,and addressed possible resistance to small-molecule inhibitors by degrading the entire STAT3 protein.In this review,we presented a brief introduction to STAT3 and its functions in various cancers,and systematically overviewed the pharmacological effects of inhibitors targeting different domains of STAT3 in the last three years,the structural characterization of the main scaffold,the design strategies,and the pharmacological activities of the substituents.Also,the binding patterns and interactions of some inhibitors with STAT3 were analyzed in detail and the recent advances in STAT3 degraders are also summarized.We anticipate that this perspective will contribute to the design and optimize more novel effective and specific STAT3 inhibitors or degraders for carcinoma treatment.
