Synthesis and biological evaluation of heterocyclic bis-aryl amides as novel Src homology 2 domain containing protein tyrosine phosphatase-2 (SHP2) inhibitors
Synthesis and biological evaluation of heterocyclic bis-aryl amides as novel Src homology 2 domain containing protein tyrosine phosphatase-2 (SHP2) inhibitors
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杂环双芳基酰胺作为新型 Src 同源 2 结构域的蛋白酪氨酸磷酸酶 2 (SHP2) 抑制剂的合成和生物学评价
DOI：
10.1016/j.bmcl.2020.127170
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发表时间：
2020-06-01
影响因子：
2.7
通讯作者：
Wang, Wen-Long
中科院分区：
文献类型：
--
作者：
Satheeshkumar, Rajendran;Zhu, Rui;Wang, Wen-Long
含有蛋白酪氨酸磷酸酶 2 (SHP2) 的 Src 同源 2 结构域是包括 PD-L1/PD-1 通路在内的致癌细胞信号级联的汇聚节点。因此，SHP2 已成为新型抗癌药物的引人注目的靶标。将PTP1B抑制剂1中的一个苯环替换为杂环，得到一系列杂环双芳基酰胺衍生物。代表性化合物7b显示出SHP2抑制活性，IC50为2.63+/-0.08μM，对SHP2的选择性比TCPTP高约4倍，并且对SHP1和PTP1B没有可检测到的活性。这些初步结果可以为开发具有最佳效力和改善药理特性的新型 SHP2 抑制剂提供可能的机会。
The Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) is a convergent node for oncogenic cell-signaling cascades including the PD-L1/PD-1 pathway. Consequently, SHP2 has emerged as a compelling target for novel anti-cancer agents. Replacing one of phenyl ring in PTP1B inhibitor 1 with heterocyclic ring led to a series of heterocyclic bis-aryl amide derivatives. The representative compound 7b displayed SHP2 inhibitory activity with IC50 of 2.63 +/- 0.08 mu M, exhibited about 4-fold selectivity for SHP2 over TCPTP and had no detectable activity against SHP1 and PTP1B. These preliminary results could provide a possible opportunity for the development of novel SHP2 inhibitors with optimal potency and improved pharmacological properties.