2. Academic Validation
  3. Discovery of N-benzylarylamide derivatives as novel tubulin polymerization inhibitors capable of activating the Hippo pathway

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

  • Eur J Med Chem. 2022 Oct 5;240:114583. doi: 10.1016/j.ejmech.2022.114583.
Jian Song 1,  Sheng-Hui Wang 2,  Chun-Hong Song 3,  Wei-Xin Zhang 3,  Jun-Xia Zhu 3,  Xin-Yi Tian 2,  Xiang-Jing Fu 3,  Yan Xu 2,  Cheng-Yun Jin 4,  Sai-Yang Zhang 5
Affiliations

Affiliations

  • 1 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.
  • 2 School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
  • 3 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.
  • 4 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. Electronic address: cyjin@zzu.edu.cn.
  • 5 School of Basic Medical 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; Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou, 450001, China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210023, Jiangsu, People's Republic of China. Electronic address: saiyangz@zzu.edu.cn.
PMID: 35834904 DOI: 10.1016/j.ejmech.2022.114583
Abstract

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.

Keywords

Antiproliferative activities; CA-4; Colchicine binding site; Hippo pathway; N-benzylarylamide; YAP.

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