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SD-91 as A Potent and Selective STAT3 Degrader Capable of Achieving Complete and Long-Lasting Tumor Regression.

ABSTRACT: Signal transducer and activator of transcription 3 (STAT3) is an attractive cancer therapeutic target. We report herein our extensive in vitro and in vivo evaluations of SD-91, the product of the hydrolysis of our previously reported STAT3 degrader SD-36. SD-91 binds to STAT3 protein with a high affinity and displays >300-fold selectivity over other STAT family protein members. SD-91 potently and effectively induces degradation of STAT3 protein and displays a high selectivity over other STAT members and >7000 non-STAT proteins in cells. A single administration of SD-91 selectively depletes STAT3 protein in tumor tissues with a persistent effect. SD-91 achieves complete and long-lasting tumor regression in the MOLM-16 xenograft model in mice even with weekly administration. Hence, SD-91 is a potent, highly selective, and efficacious STAT3 degrader for extensive evaluations for the treatment of human cancers and other diseases for which STAT3 plays a key role.

SUBMITTER: Zhou H 

PROVIDER: S-EPMC8201759 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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SD-91 as A Potent and Selective STAT3 Degrader Capable of Achieving Complete and Long-Lasting Tumor Regression.

Zhou Haibin H   Bai Longchuan L   Xu Renqi R   McEachern Donna D   Chinnaswamy Krishnapriya K   Li Ruiting R   Wen Bo B   Wang Mi M   Yang Chao-Yie CY   Meagher Jennifer L JL   Sun Duxin D   Stuckey Jeanne A JA   Wang Shaomeng S  

ACS medicinal chemistry letters 20210510 6

Signal transducer and activator of transcription 3 (STAT3) is an attractive cancer therapeutic target. We report herein our extensive <i>in vitro</i> and <i>in vivo</i> evaluations of SD-91, the product of the hydrolysis of our previously reported STAT3 degrader SD-36. SD-91 binds to STAT3 protein with a high affinity and displays >300-fold selectivity over other STAT family protein members. SD-91 potently and effectively induces degradation of STAT3 protein and displays a high selectivity over  ...[more]

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