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

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) dis...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:European journal of medicinal chemistry 2022-10, Vol.240, p.114583-114583, Article 114583
Hauptverfasser: Song, Jian, Wang, Sheng-Hui, Song, Chun-Hong, Zhang, Wei-Xin, Zhu, Jun-Xia, Tian, Xin-Yi, Fu, Xiang-Jing, Xu, Yan, Jin, Cheng-Yun, Zhang, Sai-Yang
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung: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. [Display omitted] •Novel N-benzylarylamide derivatives were prepared.•Compound 875 displayed excellent antiproliferative activity.•Compound 875 inhibited tubulin polymerization by binding to the colchicine site.•Compound 875 activated the Hippo pathway.•Compound 875 induced cell cycle arrest and cells apoptosis in gastric cells.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2022.114583