Discovery of SD-436: A Potent, Highly Selective and Efficacious STAT3 PROTAC Degrader Capable of Achieving Complete and Long-Lasting Tumor Regression

IF 5.3 2区材料科学 Q2 MATERIALS SCIENCE, MULTIDISCIPLINARY

ACS Applied Nano Materials Pub Date : 2024-11-07 DOI:10.1021/acs.jmedchem.4c01946

Renqi Xu, Haibin Zhou, Longchuan Bai, Donna McEachern, Dimin Wu, Ranjan Kumar Acharyya, Mi Wang, Jelena Tošović, Chao-Yie Yang, Krishnapriya Chinnaswamy, Jennifer L. Meagher, Jeanne A. Stuckey, Cai Liu, Meilin Wang, Bo Wen, Duxin Sun, Shaomeng Wang

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Abstract

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.

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发现 SD-436：一种强效、高选择性和高效的 STAT3 PROTAC 降解剂，可实现肿瘤的完全和长期消退

STAT3 是癌症和其他人类疾病的诱人治疗靶点。我们以前曾报道过发现了强效、选择性和高效的 PROTAC STAT3 降解剂 SD-36 和 SD-91。在这项研究中，我们利用一种新型的、具有优异化学稳定性的高亲和性 STAT3 配体和脑龙配体，设计并合成了一系列新型 STAT3 降解剂。通过努力，我们发现了 SD-436，它是一种高效力、高选择性的 STAT3 降解剂。单次静脉注射 5 毫克/千克的 SD-436 可有效诱导小鼠原生和异种移植肿瘤组织中 STAT3 的快速、完全和持久消耗。在白血病和淋巴瘤异种移植小鼠模型中，即使采用每周给药一次的给药计划，SD-436也能实现完全、持久的肿瘤消退。SD-436 是一种很有前景的 STAT3 降解剂，可作为治疗人类癌症和其他人类疾病的新疗法进行高级临床前开发。

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来源期刊

ACS Applied Nano Materials Multiple-

CiteScore

8.30

自引率

3.40%

发文量

1601

期刊介绍： ACS Applied Nano Materials is an interdisciplinary journal publishing original research covering all aspects of engineering, chemistry, physics and biology relevant to applications of nanomaterials. The journal is devoted to reports of new and original experimental and theoretical research of an applied nature that integrate knowledge in the areas of materials, engineering, physics, bioscience, and chemistry into important applications of nanomaterials.