发现新型 N-苄基芳酰胺衍生物作为微管聚合抑制剂，能够激活 Hippo 通路。
Discovery of N-benzylarylamide derivatives as novel tubulin polymerization inhibitors capable of activating the Hippo pathway.
机构信息
School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China; Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, 450001, China.
School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
出版信息
Eur J Med Chem. 2022 Oct 5;240:114583. doi: 10.1016/j.ejmech.2022.114583. Epub 2022 Jul 7.
Novel N-benzylarylamide saderivatives were designed and synthesized, and their antiproliferative activities were explored. Some of 51 target compounds exhibited potent inhibitory activities against MGC-803, HCT-116 and KYSE450 cells with IC values in two-digit nanomolar. Compound I-33 (MY-875) displayed the most potent antiproliferative activities against MGC-803, HCT-116 and KYSE450 cells (IC = 0.027, 0.055 and 0.067 μM, respectively) and possessed IC values ranging from 0.025 to 0.094 μM against other 11 cancer cell lines. Further mechanism studies indicated that compound I-33 (MY-875) inhibited tubulin polymerization (IC = 0.92 μM) by targeting the colchicine bingding site of tubulin. Compound I-33 (MY-875) disrupted the construction of the microtubule networks and affected the mitosis in MGC-803 and SGC-7901 cells. In addition, although it acted as a colchicine binding site inhibitor, compound I-33 (MY-875) also activated the Hippo pathway to promote the phosphorylation status of MST and LATS, resulting in the YAP degradation in MGC-803 and SGC-7901 cells. Due to the degradation of YAP, the expression levels of TAZ and Axl decreased. Because of the dual actions on colchicine binding site and Hippo pathway, compound I-33 (MY-875) dose-dependently inhibited cell colony formatting ability, arrested cells at the G2/M phase and induced cells apoptosis in MGC-803 and SGC-7901 cells. Moreover, compound I-33 (MY-875) could regulate the levels of cell cycle and apoptosis regulatory proteins in MGC-803 and SGC-7901 cells. Furthermore, molecular docking analysis suggested that the hydrogen bond and hydrophobic interactions made compound I-33 (MY-875) well bind into the colchicine binding site of tubulin. Collectively, compound I-33 (MY-875) is a novel anti-gastric cancer agent and deserves to be further investigated for cancer therapy by targeting the colchicine binding site of tubulin and activating the Hippo pathway.
新型 N-苄基芳酰胺衍生物被设计和合成，并探索了它们的抗增殖活性。在两位数纳摩尔浓度下，51 种目标化合物中的一些对 MGC-803、HCT-116 和 KYSE450 细胞具有很强的抑制活性，IC 值在纳摩尔浓度范围内。化合物 I-33（MY-875）对 MGC-803、HCT-116 和 KYSE450 细胞表现出最强的抗增殖活性（IC 分别为 0.027、0.055 和 0.067μM），对其他 11 种癌细胞系的 IC 值范围为 0.025 至 0.094μM。进一步的机制研究表明，化合物 I-33（MY-875）通过靶向微管蛋白的秋水仙碱结合位点抑制微管蛋白聚合（IC = 0.92μM）。化合物 I-33（MY-875）破坏微管网络的构建，并影响 MGC-803 和 SGC-7901 细胞的有丝分裂。此外，尽管它作为秋水仙碱结合位点抑制剂起作用，但化合物 I-33（MY-875）还激活 Hippo 通路以促进 MST 和 LATS 的磷酸化状态，导致 MGC-803 和 SGC-7901 细胞中 YAP 的降解。由于 YAP 的降解，TAZ 和 Axl 的表达水平降低。由于对秋水仙碱结合位点和 Hippo 通路的双重作用，化合物 I-33（MY-875）剂量依赖性地抑制细胞集落形成能力，使细胞在 G2/M 期停滞，并诱导 MGC-803 和 SGC-7901 细胞凋亡。此外，化合物 I-33（MY-875）可以调节 MGC-803 和 SGC-7901 细胞中细胞周期和凋亡调节蛋白的水平。此外，分子对接分析表明，氢键和疏水相互作用使化合物 I-33（MY-875）能够很好地结合到微管蛋白的秋水仙碱结合位点。总之，化合物 I-33（MY-875）是一种新型的抗胃癌药物，通过靶向微管蛋白的秋水仙碱结合位点和激活 Hippo 通路，值得进一步研究用于癌症治疗。
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