A Potent and Selective Small-Molecule Degrader of STAT3 Achieves Complete Tumor Regression In Vivo
A Potent and Selective Small-Molecule Degrader of STAT3 Achieves Complete Tumor Regression In Vivo
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DOI：
10.1016/j.ccell.2019.10.002
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发表时间：
2019-11-11
期刊：
影响因子：
50.3
通讯作者：
Wang, Shaomeng
中科院分区：
文献类型：
--
作者：
Bai, Longchuan;Zhou, Haibin;Wang, Shaomeng
信号转导和转录激活因子3（STAT 3）是一个有吸引力的肿瘤治疗靶点。在这里，我们报告了SD-36的发现，这是一种STAT 3的小分子降解剂。SD-36在体外和体内均能有效诱导STAT 3蛋白降解，并表现出比其他STAT成员更高的选择性。在白血病和淋巴瘤细胞中，STAT 3的诱导降解导致其转录网络的强烈抑制。SD-36通过诱导细胞周期停滞和/或凋亡抑制急性髓性白血病和间变性大细胞淋巴瘤细胞系亚群的生长。SD-36在耐受良好的剂量方案下，在多个异种移植小鼠模型中实现了完全和持久的肿瘤消退。因此，STAT 3蛋白的降解是一种有前途的癌症治疗策略。
Signal transducer and activator of transcription 3 (STAT3) is an attractive cancer therapeutic target. Here we report the discovery of SD-36, a small-molecule degrader of STAT3. SD-36 potently induces the degradation of STAT3 protein in vitro and in vivo and demonstrates high selectivity over other STAT members. Induced degradation of STAT3 results in a strong suppression of its transcription network in leukemia and lymphoma cells. SD-36 inhibits the growth of a subset of acute myeloid leukemia and anaplastic large-cell lymphoma cell lines by inducing cell-cycle arrest and/or apoptosis. SD-36 achieves complete and long-lasting tumor regression in multiple xenograft mouse models at well-tolerated dose schedules. Degradation of STAT3 protein, therefore, is a promising cancer therapeutic strategy.