A small molecule compound targeting STAT3 DNA-binding domain inhibits cancer cell proliferation, migration, and invasion.
A small molecule compound targeting STAT3 DNA-binding domain inhibits cancer cell proliferation, migration, and invasion.
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DOI：
10.1021/cb500071v
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发表时间：
2014-05-16
影响因子：
4
通讯作者：
Zhang, Jian-Ting
中科院分区：
文献类型：
--
作者：
Huang, Wei;Dong, Zizheng;Wang, Fang;Peng, Hui;Liu, Jing-Yuan;Zhang, Jian-Ting
信号转导和转录激活因子3(STAT3)通过调节多个下游靶基因的表达，在肿瘤侵袭性的多个方面发挥重要作用，包括迁移、侵袭、生存、自我更新、血管生成和肿瘤细胞免疫逃避。STAT3在许多恶性肿瘤中呈结构性激活，它的激活与高组织学分级和晚期癌症分期有关。因此，抑制STAT3有望成为治疗晚期和转移性癌症的吸引人的策略。在这里，我们使用改进的虚拟筛选策略，通过靶向STAT3的DNA结合结构域，在S3-54中鉴定了一个STAT3抑制剂。InS3-54优先抑制肿瘤细胞的增殖，抑制肿瘤细胞的迁移和侵袭。生化分析表明，InS3-54选择性地抑制STAT3与DNA的结合，而不影响STAT3的激活和二聚化。此外，inS3-54还能抑制STAT3下游靶基因的表达，抑制STAT3与染色质的原位结合。因此，INS3-54代表了一种新的针对STAT3的DNA结合域的特异性抑制剂的开发和潜在的癌症治疗方法。
Signal transducer and activator of transcription 3 (STAT3) plays important roles in multiple aspects of cancer aggressiveness including migration, invasion, survival, self-renewal, angiogenesis, and tumor cell immune evasion by regulating the expression of multiple downstream target genes. STAT3 is constitutively activated in many malignant tumors and its activation is associated with high histological grade and advanced cancer stages. Thus, inhibiting STAT3 promises an attracting strategy for treatment of advanced and metastatic cancers. Herein, we identified a STAT3 inhibitor, inS3-54, by targeting the DNA-binding domain of STAT3 using an improved virtual screening strategy. InS3-54 preferentially suppresses proliferation of cancer over non-cancer cells and inhibits migration and invasion of malignant cells. Biochemical analyses show that inS3-54 selectively inhibits STAT3 binding to DNA without affecting the activation and dimerization of STAT3. Furthermore, inS3-54 inhibits expression of STAT3 downstream target genes and STAT3 binding to chromatin in situ. Thus, inS3-54 represents a novel probe for development of specific inhibitors targeting the DNA-binding domain of STAT3 and a potential therapeutic for cancer treatments.
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