苯并[c][1,2,5]噻二唑衍生物：一类新型强效含Src同源2结构域蛋白酪氨酸磷酸酶2（SHP2）抑制剂。
Benzo[c][1,2,5]thiadiazole derivatives: A new class of potent Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) inhibitors.
作者信息
Wang Wen-Long, Chen Xiao-Yu, Gao Ya, Gao Li-Xin, Sheng Li, Zhu Jingyu, Xu Lei, Ding Zhen-Zhong, Zhang Chao, Li Jing-Ya, Li Jia, Zhou Yu-Bo
机构信息
School of Pharmaceutical Sciences, Jiangnan University, Wuxi 214122, China; State Key Laboratory of Drug Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
School of Pharmaceutical Sciences, Jiangnan University, Wuxi 214122, China.
出版信息
Bioorg Med Chem Lett. 2017 Dec 1;27(23):5154-5157. doi: 10.1016/j.bmcl.2017.10.059. Epub 2017 Oct 26.
The Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) is an oncogenic phosphatase linked to various kinds of cancers. Consequently, SHP2 has emerged as a promising target for novel anti-cancer agents. Using scaffold-hopping strategy, a series of benzo[c][1,2,5]thiadiazole derivatives was designed from PTP1B inhibitors with 1H-2,3-Dihydroperimidine motif, synthesized and evaluated their biological activities against PTP1B and SHP2. Among them, the representative compound 11g displayed SHP2 inhibitory activity with IC of 2.11 ± 0.99 μM, exhibited 2.02-fold and 25-fold selectivity for SHP2 over SHP1 and PTP1B respectively and had no visible activity against TCPTP. These preliminary results could provide a possible opportunity for the development of novel SHP2 inhibitors with optimal potency and improved pharmacological properties.
含Src同源2结构域的蛋白酪氨酸磷酸酶2（SHP2）是一种与多种癌症相关的致癌磷酸酶。因此，SHP2已成为新型抗癌药物的一个有前景的靶点。采用骨架跳跃策略，从具有1H-2,3-二氢嘧啶基序的PTP1B抑制剂设计了一系列苯并[c][1,2,5]噻二唑衍生物，合成并评估了它们对PTP1B和SHP2的生物活性。其中，代表性化合物11g对SHP2具有抑制活性，IC50为2.11±0.99μM，对SHP2的选择性分别是对SHP1和PTP1B的2.02倍和25倍，对TCPTP无明显活性。这些初步结果可能为开发具有最佳效力和改善药理特性的新型SHP2抑制剂提供机会。
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