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.

信号转导子和转录激活子 5 (STAT5) 是一个有吸引力的治疗靶点，但成功靶向 STAT5 已被证明是困难的。在此，我们报告了 AK-2292 作为第一个有效且选择性的 STAT5A 和 STAT5B 亚型小分子降解剂的开发情况。AK-2292 诱导 STAT5A/B 蛋白降解，其选择性优于所有其他 STAT 蛋白和 6,000 多种非 STAT 蛋白，从而选择性抑制细胞中的 STAT5 活性。AK-2292 可有效诱导正常小鼠组织和人类慢性粒细胞白血病 (CML) 异种移植组织中的 STAT5 耗竭，并在两种 CML 异种移植小鼠模型中以耐受良好的剂量方案实现肿瘤消退。AK-2292 不仅是研究 STAT5 生物学以及选择性 STAT5 蛋白消耗和抑制的治疗潜力的强大研究工具，而且还是最终开发 STAT5 靶向疗法的有前途的先导化合物。