Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA.
Department of Internal Medicine, University of Michigan, Medical School, Ann Arbor, MI, USA.
Nat Chem Biol. 2023 Jun;19(6):703-711. doi: 10.1038/s41589-022-01248-4. Epub 2023 Feb 2.
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 被证明是困难的。在这里，我们报告了 AK-2292 的开发，它是一种首个强效和选择性的小分子降解剂，可降解 STAT5A 和 STAT5B 同工型。AK-2292 诱导 STAT5A/B 蛋白降解，对所有其他 STAT 蛋白和超过 6000 种非 STAT 蛋白具有出色的选择性，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慢性髓性白血病（CML）异种移植组织中 STAT5 的耗竭，并在两种 CML 异种移植小鼠模型中以可耐受的剂量方案实现肿瘤消退。AK-2292 不仅是一种强大的研究工具，可用于研究 STAT5 的生物学以及选择性 STAT5 蛋白耗竭和抑制的治疗潜力，而且还是一种有前途的先导化合物，可最终开发出针对 STAT5 的治疗方法。
