A potent and selective small-molecule degrader of STAT3 achieves complete tumor regression in vivo

Signal transducer and activator of transcription 3 (STAT3) is an attractive cancer therapeutic target. We report herein 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 represents a promising cancer therapeutic strategy. Global gene transcription profiling was performed in MOLM-16 and SU-DHL-1 cell lines treated with DMSO, SD36 (1000 nmol/L) or SD36Me (1000 nmol/L) for 8 and 24 hours. Independent biological replicates (such as DMSO_8h and DMSO_24h) were analyzed for each cell line under each condition. DMSO-treated samples were used as controls.

信号转导与转录激活因子3（Signal transducer and activator of transcription 3，STAT3）是极具潜力的癌症治疗靶点。本研究在此报道了靶向STAT3的小分子降解剂SD-36的发现：SD-36可在体外及体内高效诱导STAT3蛋白降解，且相较于其他STAT家族成员展现出优异的选择性。STAT3的诱导降解可显著抑制白血病与淋巴瘤细胞内其下游转录调控网络的功能。SD-36可通过诱导细胞周期阻滞与（或）细胞凋亡，抑制部分急性髓系白血病及间变性大细胞淋巴瘤细胞系的增殖。在给药耐受性良好的剂量方案下，SD-36可在多种异种移植小鼠模型中实现完全且持久的肿瘤消退。因此，靶向STAT3蛋白的降解策略有望成为极具前景的癌症治疗手段。
本研究对经二甲基亚砜（Dimethyl sulfoxide，DMSO）、SD36（1000 nmol/L）或SD36Me（1000 nmol/L）分别处理8小时与24小时的MOLM-16及SU-DHL-1细胞系开展了全转录组表达谱分析。针对每种处理条件下的每种细胞系，均设置独立生物学重复（如DMSO_8h组与DMSO_24h组）并进行检测分析。以DMSO处理的样本作为对照。