2. Academic Validation
  3. Optimization of WZ4003 as NUAK inhibitors against human colorectal cancer

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.
Huali Yang 1,  Xiaobing Wang 2,  Cheng Wang 2,  Fucheng Yin 2,  Lailiang Qu 2,  Cunjian Shi 2,  Jinhua Zhao 2,  Shang Li 2,  Limei Ji 2,  Wan Peng 2,  Heng Luo 2,  Maosheng Cheng 3,  Lingyi Kong 4
Affiliations

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: [email protected].
  • 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: [email protected].
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.

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