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.
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.
Eur J Med Chem. 2021 Jan 15;210:113080. doi: 10.1016/j.ejmech.2020.113080. Epub 2020 Dec 4.
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.
NUAK，蛋白激酶 AMPK（AMP 激活的蛋白激酶）家族的成员之一，可被 LKB1（肝激酶 B1）肿瘤抑制蛋白激酶磷酸化和激活。最近的研究表明，NUAK1 是抗氧化应激反应途径的关键组成部分，抑制 NUAK1 将抑制结直肠肿瘤的生长和存活。作为一种有前途的抗癌药物靶点，开发的 NUAK 抑制剂很少。基于 NUAK 抑制剂 WZ4003，我们已经合成了一系列衍生物并对其抗癌活性进行了评估。化合物 9q，是 WZ4003 通过去除一个甲氧基得到的衍生物，是最有潜力的化合物，对 NUAK1/2 酶活性、肿瘤细胞增殖和诱导肿瘤细胞凋亡具有更强的抑制作用。通过对结直肠 SW480 异种移植瘤的体内疗效评估，9q 能更有效地抑制肿瘤生长，且在体内具有良好的安全性，因此被认为是进一步研究的合适候选药物。
