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.

中文翻译：

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STAT3的强效选择性小分子降解剂可实现体内完整的肿瘤消退。

信号转导子和转录激活子3（STAT3）是有吸引力的癌症治疗靶标。在这里，我们报告发现STAT3的小分子降解物SD-36。SD-36在体外和体内均能有效诱导STAT3蛋白降解，并显示出比其他STAT成员更高的选择性。STAT3的诱导降解导致其在白血病和淋巴瘤细胞中的转录网络受到强烈抑制。SD-36通过诱导细胞周期停滞和/或凋亡来抑制部分急性髓细胞白血病和间变性大细胞淋巴瘤细胞系的生长。SD-36在耐受良好的剂量方案下，在多种异种移植小鼠模型中实现了完整且持久的肿瘤消退。因此，STAT3蛋白的降解是一种有前途的癌症治疗策略。