一种选择性的小分子STAT5 PROTAC降解剂，在体内能够实现肿瘤退缩。
A selective small-molecule STAT5 PROTAC degrader capable of achieving tumor regression in vivo.
发表日期：2023 Feb 02
作者：
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
来源：
Nature Chemical Biology
摘要：
信号转导和激活因子5（STAT5）是一种具有吸引力的治疗靶点，但成功地针对STAT5进行治疗已被证明是困难的。在此，我们报道了AK-2292的研发，它是第一种有效且选择性的小分子降解剂，可以降解STAT5A和STAT5B亚型。AK-2292具有卓越的选择性，可以选择性地降解STAT5A/B蛋白，而不影响其他STAT蛋白和超过6,000种非STAT蛋白，从而导致对细胞中STAT5活性的选择性抑制。AK-2292能够有效地在正常小鼠组织和人类慢性髓性白血病（CML）异种移植组织中诱导STAT5的消耗，并在能够耐受的剂量表中在两个CML异种移植小鼠模型中实现肿瘤退化。AK-2292不仅是一个强大的研究工具，可以用来研究STAT5的生物学和选择性STAT5蛋白消耗和抑制的治疗潜力，还是向最终发展STAT5靶向治疗的一个有前途的主导化合物。©2023.作者（们）在Springer Nature America, Inc.的独家许可下进行。
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.