摘要/Abstract

作为细胞信号转导通路的关键节点分子, 含SH2结构域蛋白酪氨酸磷酸酶1 (SHP1)是潜在的抗肿瘤靶点. 已知的SHP1抑制剂屈指可数. 设计并合成了11个5-苯基-1,3,4-噻二唑衍生物. 活性测试结果表明, 部分衍生物对SHP1显示了一定强度的抑制活性. 其中, 化合物5b [IC₅₀=(1.33±0.16) μmol/L]对SHP1显示了中等强度的抑制活性, 对PTP1B和TCPTP不显示抑制活性, 对SHP2显示了2倍的选择性, 为发现新型SHP1抑制剂提供了新的骨架类型.
关键词: 5-苯基-1,3,4-噻二唑衍生物, 含SH2结构域蛋白酪氨酸磷酸酶1 (SHP1), 抑制剂, 构效关系
The Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP1) is a convergent node for oncogenic cell-signaling cascades. Consequently, SHP1 represents a potential target for drug development in cancer treatment. Meanwhile only countable SHP1 inhibitors have been reported. A new type of SHP1 inhibitors with 5-phenyl-1,3,4-thiadiazole scaffold was developed. The representative compound 5b exhibited SHP1 inhibitory activity with IC₅₀ of (1.33±0.16) μmol/L, exhibited about 2-fold selectivity for SHP1 over SHP2, and had no detectable activity against PTP1B and TCPTP, and offered a novel scaffold to develop new SHP1 inhibitors.
Key words: 5-phenyl-1,3,4-thiadiazole derivatives, Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP1), inhibitors, structure-activity relationships


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