Optimization of WZ4003 as NUAK inhibitors against human colorectal cancer

Huali Yang; Xiaobing Wang; Cheng Wang; Fucheng Yin; Lailiang Qu; Cunjian Shi; Jinhua Zhao; Shang Li; Limei Ji; Wan Peng; Heng Luo; Maosheng Cheng; Lingyi Kong

doi:10.1016/j.ejmech.2020.113080

Optimization of WZ4003 as NUAK inhibitors against human colorectal cancer

Eur J Med Chem. 2021 Jan 15:210:113080. doi: 10.1016/j.ejmech.2020.113080. Epub 2020 Dec 4.

Authors

Huali Yang¹, Xiaobing Wang², Cheng Wang², Fucheng Yin², Lailiang Qu², Cunjian Shi², Jinhua Zhao², Shang Li², Limei Ji², Wan Peng², Heng Luo², Maosheng Cheng³, Lingyi Kong⁴

Affiliations

¹ Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, China.
² Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China.
³ School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: mscheng@syphu.edu.cn.
⁴ Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: cpu_lykong@126.com.

PMID: 33310286
DOI: 10.1016/j.ejmech.2020.113080

Abstract

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.

Keywords: AMP-Activated protein kinase (AMPK); Colorectal cancer; NUAK; WZ4003 derivatives.

MeSH terms

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 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
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

Substances

Anilides
Antineoplastic Agents
Protein Kinase Inhibitors
Pyrimidines
Repressor Proteins
WZ4003
Protein Kinases
NUAK1 protein, human
NUAK2 protein, human
Protein Serine-Threonine Kinases