Transient receptor potential canonical 6 (TRPC6) proteins form receptor-operated Ca2+-permeable channels, which have been thought to bring benefit to the treatment of diseases, including cancer. However, selective antagonists for TRPC channels are rare and none of them has been tested against gastric cancer. Compound 14a and analogs were synthesized by chemical elaboration of previously reported TRPC3/6/7 agonist 4o. 14a had very weak agonist activity at TRPC6 expressed in HEK293 cells but exhibited strong inhibition on both 4o-mediated and receptor-operated activation of TRPC6 with an IC50 of about 1 μM. When applied to the culture media, 14a suppressed proliferation of AGS and MKN45 cells with IC50 values of 17.1 ± 0.3 and 18.5 ± 1.0 μM, respectively, and inhibited tube formation and migration of cultured human endothelial cells. This anti-tumor effect on gastric cancer was further verified in xenograft models using nude mice. This study has found a new tool compound which shows excellent therapeutic potential against human gastric cancer most likely through targeting TRPC6 channels.

中文翻译：

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吡唑并[1,5-a]嘧啶TRPC6拮抗剂用于治疗胃癌。

瞬时受体电位规范 6 (TRPC6) 蛋白形成受体操纵的 Ca2+ 通透通道，被认为有益于治疗包括癌症在内的疾病。然而，TRPC 通道的选择性拮抗剂很少见，而且尚未针对胃癌进行过测试。化合物 14a 和类似物是通过先前报道的 TRPC3/6/7 激动剂 4o 的化学精制合成的。14a对HEK293细胞中表达的TRPC6具有非常弱的激动剂活性，但对4o介导的和受体操作的TRPC6激活表现出强烈的抑制作用，IC50约为1μM。当应用于培养基时，14a 抑制 AGS 和 MKN45 细胞的增殖，IC50 值分别为 17.1 ± 0.3 和 18.5 ± 1.0 μM，并抑制培养的人内皮细胞的管形成和迁移。这种对胃癌的抗肿瘤作用在裸鼠异种移植模型中得到了进一步验证。这项研究发现了一种新的工具化合物，它很可能通过靶向 TRPC6 通道而显示出针对人类胃癌的优异治疗潜力。