Optimization of WZ4003 as NUAK inhibitors against human colorectal cancer

• Published in: European journal of medicinal chemistry 2021-01, Vol.210, p.113080, Article 113080
• Main Authors: Yang, Huali, Wang, Xiaobing, Wang, Cheng, Yin, Fucheng, Qu, Lailiang, Shi, Cunjian, Zhao, Jinhua, Li, Shang, Ji, Limei, Peng, Wan, Luo, Heng, Cheng, Maosheng, Kong, Lingyi
• Format: Article
• Language: English
• Subjects: AMP-Activated protein kinase (AMPK); Anilides - chemical synthesis; Anilides - chemistry; Anilides - pharmacology; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cell Cycle - drug effects; Cell Proliferation - drug effects; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Structure; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; NUAK; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Kinases - metabolism; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - metabolism; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Repressor Proteins - antagonists & inhibitors; Repressor Proteins - metabolism; Structure-Activity Relationship; Tumor Cells, Cultured; WZ4003 derivatives
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2020.113080

NUAK, the member of AMPK (AMP-activated protein kinase) family of protein kinases, is phosphorylated and activated by the LKB1 (liver kinase B1) tumor suppressor protein kinase. Recent work has indicated that NUAK1 is a key component of the antioxidant stress response pathway, and the inhibition of NUAK1 will suppress the growth and survival of colorectal tumors. As a promising target for anticancer drugs, few inhibitors of NUAK were developed. With this goal in mind, based on NUAK inhibitor WZ4003, a series of derivatives has been synthesized and evaluated for anticancer activity. Compound 9q, a derivative of WZ4003 by removing a methoxy group, was found to be the most potential one with stronger inhibitory against NUAK1/2 enzyme activity, tumor cell proliferation and inducing apoptosis of tumor cells. By in vivo efficacy evaluations of colorectal SW480 xenografts, 9q suppresses tumor growth more effectively with an excellent safety profile in vivo and is therefore seen as a suitable candidate for further investigation. [Display omitted] •A series of WZ4003 derivatives were synthesized and evaluated for NUAK inhibition and anti-tumor activities.•The necessity of piperazine ring and redundance of methoxy on the benzene ring for NUAK inhibition were confirmed.•The derivative 9q could be an excellent NUAK inhibitor and a promising candidate for the development of anti-tumor drugs.