A selective small-molecule STAT5 PROTAC degrader capable of achieving tumor regression in vivo.

Nature chemical biology 2023 Jun

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Signal transducer and activator of transcription 5 (STAT5) is an attractive therapeutic target, but successful targeting of STAT5 has proved to be difficult. Here we report the development of AK-2292 as a first, potent and selective small-molecule degrader of both STAT5A and STAT5B isoforms. AK-2292 induces degradation of STAT5A/B proteins with an outstanding selectivity over all other STAT proteins and more than 6,000 non-STAT proteins, leading to selective inhibition of STAT5 activity in cells. AK-2292 effectively induces STAT5 depletion in normal mouse tissues and human chronic myeloid leukemia (CML) xenograft tissues and achieves tumor regression in two CML xenograft mouse models at well-tolerated dose schedules. AK-2292 is not only a powerful research tool with which to investigate the biology of STAT5 and the therapeutic potential of selective STAT5 protein depletion and inhibition but also a promising lead compound toward ultimate development of a STAT5-targeted therapy. © 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.

Citation

Atsunori Kaneshige, Longchuan Bai, Mi Wang, Donna McEachern, Jennifer L Meagher, Renqi Xu, Yu Wang, Wei Jiang, Hoda Metwally, Paul D Kirchhoff, Lijie Zhao, Hui Jiang, Meilin Wang, Bo Wen, Duxin Sun, Jeanne A Stuckey, Shaomeng Wang. A selective small-molecule STAT5 PROTAC degrader capable of achieving tumor regression in vivo. Nature chemical biology. 2023 Jun;19(6):703-711