2‐anilino‐4‐amino‐5‐aroylthiazole‐type compound AS7128 inhibits lung cancer growth through decreased iASPP and p53 interaction

• Published in: Cancer science Vol. 109; no. 3; pp. 832 - 842
• Main Authors: Cheng, Hao‐Wei, Chein, Rong‐Jie, Cheng, Ting‐Jen, Wu, Pei‐Shan, Wu, Hsin‐Yi, Hung, Pei‐Fang, Wang, Chia‐Jen, Hsu, Yuan‐Ling, Wong, Jau‐Min, Yuan, Ang, Wong, Chi‐Huey, Yang, Pan‐Chyr, Pan, Szu‐Hua
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.03.2018; John Wiley and Sons Inc
• Subjects: A549 Cells; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Apoptosis; Cancer therapies; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Cell cycle; Cell division; Cell growth; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival; Gene Expression Regulation, Neoplastic; Genes; Humans; iASPP; Intracellular Signaling Peptides and Proteins - metabolism; Laboratory animals; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Mice; Mitosis; Original; p53; p53 Protein; Peptides; Protein Binding - drug effects; Proteins; Repressor Proteins - metabolism; Therapeutic applications; Thiazoles - administration & dosage; Thiazoles - pharmacology; Tumor Suppressor Protein p53 - metabolism; Xenograft Model Antitumor Assays; United States > US; Taiwan; lung cancer; apoptosis; cell cycle; iASPP; p53
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/cas.13489

Lung cancer is the leading cause of cancer‐related death worldwide. Thus, developing novel therapeutic agents has become critical for lung cancer treatment. In this study, compound AS7128 was selected from a 2‐million entry chemical library screening and identified as a candidate drug against non‐small cell lung cancer in vitro and in vivo. Further investigation indicated that AS7128 could induce cell apoptosis and cell cycle arrest, especially in the mitosis stage. In addition, we also found that iASPP, an oncogenic protein that functionally inhibits p53, might be associated with AS7128 through mass identification. Further exploration indicated that AS7128 treatment could restore the transactivation ability of p53 and, thus, increase the expressions of its downstream target genes, which are related to cell cycle arrest and apoptosis. This occurs through disruption of the interactions between p53 and iASPP in cells. Taken together, AS7128 could bind to iASPP, disrupt the interaction between iASPP and p53, and result in cell cycle arrest and apoptosis. These findings may provide new insight for using iASPP as a therapeutic target for non‐small cell lung cancer treatment. From a 2‐million entry chemical library screening, we identified compound AS7128 as a candidate drug that against non‐small cell lung cancer. AS7128 could bind to iASPP, enhance the transactivation ability of p53 through decreasing the interaction between iASPP and p53, drive the gene expression of p53 downstream genes, and induce cell cycle M phase arrest and apoptosis.