Kaneshige Atsunori, Bai Longchuan, Wang Mi, McEachern Donna, Meagher Jennifer L, Xu Renqi, Kirchhoff Paul D, Wen Bo, Sun Duxin, Stuckey Jeanne A, Wang Shaomeng
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.
Department of Internal Medicine, Medical School, University of Michigan, Ann Arbor, Michigan 48109, United States.
J Med Chem. 2023 Feb 23;66(4):2717-2743. doi: 10.1021/acs.jmedchem.2c01665. Epub 2023 Feb 3.
STAT5 is an attractive therapeutic target for human cancers. We report herein the discovery of a potent and selective STAT5 degrader with strong antitumor activity . We first obtained small-molecule ligands with sub-micromolar to low micromolar binding affinities to STAT5 and STAT6 SH2 domains and determined co-crystal structures of three such ligands in complex with STAT5A. We successfully transformed these ligands into potent and selective STAT5 degraders using the PROTAC technology with AK-2292 as the best compound. AK-2292 effectively induces degradation of STAT5A, STAT5B, and phosphorylated STAT5 proteins in a concentration- and time-dependent manner in acute myeloid leukemia (AML) cell lines and demonstrates excellent degradation selectivity for STAT5 over all other STAT members. It exerts potent and specific cell growth inhibitory activity in AML cell lines with high levels of phosphorylated STAT5. AK-2292 effectively reduces STAT5 protein and achieves strong antitumor activity in mice at well-tolerated dose schedules.
信号转导和转录激活因子5（STAT5）是人类癌症中一个具有吸引力的治疗靶点。我们在此报告发现了一种具有强大抗肿瘤活性的强效且选择性的STAT5降解剂。我们首先获得了对STAT5和STAT6 SH2结构域具有亚微摩尔至低微摩尔结合亲和力的小分子配体，并确定了三种此类配体与STAT5A复合物的共晶体结构。我们使用PROTAC技术成功地将这些配体转化为强效且选择性的STAT5降解剂，其中AK - 2292是最佳化合物。AK - 2292在急性髓系白血病（AML）细胞系中以浓度和时间依赖性方式有效诱导STAT5A、STAT5B和磷酸化STAT5蛋白的降解，并对STAT5表现出优于所有其他STAT成员的出色降解选择性。它在具有高水平磷酸化STAT5的AML细胞系中发挥强大且特异性的细胞生长抑制活性。AK - 2292有效降低STAT5蛋白水平，并在小鼠中以耐受性良好的剂量方案实现强大的抗肿瘤活性。
