A Potent and Selective Small-Molecule Degrader of STAT3 Achieves Complete Tumor Regression In&nbsp;Vivo

Bai, Longchuan; Zhou, Haibin; Xu, Renqi; Zhao, Yujun; Chinnaswamy, Krishnapriya; McEachern, Donna; Chen, Jianyong; Yang, Chao-Yie; Liu, Zhaomin; Wang, Mi; Liu, Liu; Jiang, Hui; Wen, Bo; Kumar, Praveen; Meagher, Jennifer L.; Sun, Duxin; Stuckey, Jeanne A.; Wang, Shaomeng

doi:10.1016/j.ccell.2019.10.002

A Potent and Selective Small-Molecule Degrader of STAT3 Achieves Complete Tumor Regression In Vivo

Journal Article · Sun Nov 10 23:00:00 EST 2019 · Cancer Cell

DOI:https://doi.org/10.1016/j.ccell.2019.10.002· OSTI ID:1708979

Bai, Longchuan; Zhou, Haibin; Xu, Renqi; Zhao, Yujun; Chinnaswamy, Krishnapriya; McEachern, Donna; Chen, Jianyong; Yang, Chao-Yie; Liu, Zhaomin; Wang, Mi; Liu, Liu; Jiang, Hui; Wen, Bo; Kumar, Praveen; Meagher, Jennifer L.; Sun, Duxin; Stuckey, Jeanne A.; Wang, Shaomeng

Signal transducer and activator of transcription 3 (STAT3) is an attractive cancer therapeutic target. Here we report the discovery of SD-36, a small-molecule degrader of STAT3. SD-36 potently induces the degradation of STAT3 protein in vitro and in vivo and demonstrates high selectivity over other STAT members. Induced degradation of STAT3 results in a strong suppression of its transcription network in leukemia and lymphoma cells. SD-36 inhibits the growth of a subset of acute myeloid leukemia and anaplastic large-cell lymphoma cell lines by inducing cell-cycle arrest and/or apoptosis. SD-36 achieves complete and long-lasting tumor regression in multiple xenograft mouse models at well-tolerated dose schedules. Degradation of STAT3 protein, therefore, is a promising cancer therapeutic strategy.

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Sponsoring Organization:: USDOE Office of Science (SC); Oncopia Therapeutics, Inc.; Rogel Cancer Center Core; National Cancer Institute (NCI); National Cancer Institute (NCI); Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1708979

Alternate ID(s):: OSTI ID: 1578219
OSTI ID: 1694213

Journal Information:: Cancer Cell, Journal Name: Cancer Cell Journal Issue: 5 Vol. 36; ISSN 1535-6108

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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