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 IC₅₀ 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.

包含蛋白酪氨酸磷酸酶2（SHP2）的Src同源2结构域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有希望的靶标。运用支架跳跃策略，从具有1H -2,3-二氢哌啶基序的PTP1B抑制剂中设计了一系列苯并[ c ] [1,2,5]噻二唑衍生物，合成并评价了它们对PTP1B和SHP2的生物学活性。其中，代表性化合物11g对SHP2的抑制活性为IC ₅₀相对于SHP1和PTP1B，SHP2的SHP2选择性为2.11±0.99μM，分别具有2.02倍和25倍的选择性，并且对TCPTP没有可见活性。这些初步结果可能为开发具有最佳效价和改善药理特性的新型SHP2抑制剂提供可能的机会。