Discovery of N-benzylarylamide derivatives as novel tubulin polymerization inhibitors capable of activating the Hippo pathway

• DOI: 10.1016/j.ejmech.2022.114583
• Publication Date: 2022-07-07T03:11:28Z
• Authors: Jian Song; Sheng-Hui Wang; Chun-Hong Song; Wei-Xin Zhang; Jun-Xia Zhu; Xin-Yi Tian; Xiang-Jing Fu; Yan Xu; Cheng-Yun Jin; Sai-Yang Zhang
• Keywords: 0301 basic medicine; 0303 health sciences; Antineoplastic Agents; Tubulin Modulators; Polymerization; 3. Good health; Molecular Docking Simulation; Structure-Activity Relationship; 03 medical and health sciences; Tubulin; Cell Line, Tumor; Hippo Signaling Pathway; Drug Screening Assays, Antitumor; Colchicine; Cell Proliferation

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 IC50 values in two-digit nanomolar. Compound I-33 (MY-875) displayed the most potent antiproliferative activities against MGC-803, HCT-116 and KYSE450 cells (IC50 = 0.027, 0.055 and 0.067 μM, respectively) and possessed IC50 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 (IC50 = 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.