Cell active and functionally-relevant small-molecule agonists of calcitonin receptor
Cell active and functionally-relevant small-molecule agonists of calcitonin receptor
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降钙素受体的细胞活性和功能相关的小分子激动剂
DOI：
10.1016/j.bioorg.2020.103596
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发表时间：
2020
影响因子：
5.1
通讯作者：
Chen Xin
中科院分区：
文献类型：
--
作者：
Zhao Shuai;Guo Shengchao;Yang Chan;Gong Zheng;Wang Yaomin;Jia Yingli;Jiang Xinyu;Xu Liwei;Shi Li;Yu Xiao;Sun Jinpeng;Zhang Yan;Chen Xin
天然降钙素（CT）受体及其肽激动剂被认为是药物发现的有效靶点。小分子激动剂SUN-B8155先前已被证明有效激活细胞CTR。本文报道了一系列由SUN-B8155衍生的化合物（S8155 1-9）的合成，并研究了它们的结构-功能关系、偏性和细胞活性。我们发现吡啶酮环上的N-羟基是G蛋白活性及其与CT受体亲和力所必需的。在所研究的化合物中，S8155-7表现出改善的G蛋白活性，而S8155-4表现出显著的β-arrestin-2信号传导偏好。最后，我们表明S8155-4和S8155-7都通过CTR激活抑制肿瘤细胞侵袭。这两种化合物有望在化学生物学研究以及靶向CT受体的药物开发工作中获得广泛应用。
The natural calcitonin (CT) receptor and its peptide agonists are considered validated targets for drug discovery. A small molecule agonist, SUN-B8155, has previously been shown to efficiently activate cellular CTR. Herein, we report the synthesis of a series of compounds (S8155 1-9) derived from SUN-B8155, and investigate the structural-functional relationship, bias properties and their cellular activity profile. We discover that theN-hydroxyl group from the pyridone ring is required for G protein activity and its affinity to the CT receptor. Among the compounds studied, S8155-7 exhibits improved G protein activity while S8155-4 displays a significant β-arrestin-2 signaling bias. Finally, we show that both S8155-4 and S8155-7 inhibit tumour cell invasion through CTR activation. These two compounds are anticipated to find extensive applications in chemical biology research as well drug development efforts targeting CT receptor.