J Med Chem. 2019 Dec 26;62(24):11280-11300. doi: 10.1021/acs.jmedchem.9b01530. Epub 2019 Dec 10.
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor and an attractive therapeutic target for cancer and other human diseases. Despite 20 years of persistent research efforts, targeting STAT3 has been very challenging. We report herein the structure-based discovery of potent small-molecule STAT3 degraders based upon the proteolysis targeting chimera (PROTAC) concept. We first designed SI-109 as a potent, small-molecule inhibitor of the STAT3 SH2 domain. Employing ligands for cereblon/cullin 4A E3 ligase and SI-109, we obtained a series of potent PROTAC STAT3 degraders, exemplified by SD-36. SD-36 induces rapid STAT3 degradation at low nanomolar concentrations in cells and fails to degrade other STAT proteins. SD-36 achieves nanomolar cell growth inhibitory activity in leukemia and lymphoma cell lines with high levels of phosphorylated STAT3. A single dose of SD-36 results in complete STAT3 protein degradation in xenograft tumor tissue and normal mouse tissues. SD-36 achieves complete and long-lasting tumor regression in the Molm-16 xenograft tumor model at well-tolerated dose-schedules. SD-36 is a potent, selective, and efficacious STAT3 degrader.
信号转导子和转录激活因子 3（STAT3）是一种转录因子，是癌症和其他人类疾病的有吸引力的治疗靶点。尽管经过 20 年的持续研究努力，靶向 STAT3 一直极具挑战性。我们在此报告了基于蛋白水解靶向嵌合体（PROTAC）概念的强效小分子 STAT3 降解剂的基于结构的发现。我们首先设计了 SI-109，作为 STAT3 SH2 结构域的有效小分子抑制剂。我们使用 cereblon/cullin 4A E3 连接酶配体和 SI-109，得到了一系列强效的 PROTAC STAT3 降解剂，以 SD-36 为例。SD-36 在细胞中以低纳摩尔浓度快速诱导 STAT3 降解，并且不会降解其他 STAT 蛋白。SD-36 在具有高磷酸化 STAT3 水平的白血病和淋巴瘤细胞系中实现了纳摩尔级的细胞生长抑制活性。单次给予 SD-36 可导致异种移植肿瘤组织和正常小鼠组织中 STAT3 蛋白完全降解。SD-36 在可耐受剂量方案下，在 Molm-16 异种移植肿瘤模型中实现了完全和持久的肿瘤消退。SD-36 是一种有效、选择性和有效的 STAT3 降解剂。
