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. [Figure not available: see fulltext.]
CITATION STYLE
Kaneshige, A., Bai, L., Wang, M., McEachern, D., Meagher, J. L., Xu, R., … Wang, S. (2023). A selective small-molecule STAT5 PROTAC degrader capable of achieving tumor regression in vivo. Nature Chemical Biology, 19(6), 703–711. https://doi.org/10.1038/s41589-022-01248-4
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