STAT3 is an attractive therapeutic target for cancer and other human diseases. We have previously reported the discovery of potent, selective, and efficacious PROTAC STAT3 degraders SD-36 and SD-91. In this study, we have designed and synthesized a novel series of STAT3 degraders using a new, high-affinity STAT3 ligand with excellent chemical stability and cereblon ligands. Our efforts led to the discovery of SD-436, a highly potent and selective STAT3 degrader. A single intravenous administration of SD-436 at 5 mg/kg effectively induces rapid, complete, and durable depletion of STAT3 in mouse native and xenograft tumor tissues. SD-436 achieves complete and long-lasting tumor regression even with a weekly dosing schedule in leukemia and lymphoma xenograft models in mice. SD-436 represents a promising STAT3 degrader for advanced preclinical development as a new therapy for the treatment of human cancers and other human diseases.

中文翻译：

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SD-436 的发现：一种有效、高选择性和有效的 STAT3 PROTAC 降解剂，能够实现完全和持久的肿瘤消退


STAT3 是癌症和其他人类疾病的有吸引力的治疗靶点。我们之前曾报道过有效、选择性和有效的 PROTAC STAT3 降解剂 SD-36 和 SD-91 的发现。在这项研究中，我们使用具有优异化学稳定性的新型高亲和力 STAT3 配体和 cereblon 配体设计并合成了一系列新型的 STAT3 降解剂。我们的努力导致了 SD-436 的发现，这是一种高效且选择性的 STAT3 降解剂。单次静脉内施用 5 mg/kg 的 SD-436 可有效诱导小鼠天然和异种移植肿瘤组织中 STAT3 的快速、完全和持久耗竭。SD-436 即使在小鼠的白血病和淋巴瘤异种移植模型中每周给药方案也能实现完全和持久的肿瘤消退。SD-436 是一种很有前途的 STAT3 降解剂，作为治疗人类癌症和其他人类疾病的新疗法，用于先进的临床前开发。