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是蛋白激酶AMPK（AMP激活的蛋白激酶）家族的成员，被LKB1（肝激酶B1）肿瘤抑制蛋白激酶磷酸化并激活。最近的工作表明，NUAK1是抗氧化应激反应途径的关键组成部分，而对NUAK1的抑制将抑制结直肠肿瘤的生长和存活。作为抗癌药物的有希望的靶标，几乎没有开发出NUAK抑制剂。出于这个目标，已基于NUAK抑制剂WZ4003合成了一系列衍生物并评估了其抗癌活性。发现化合物9q是WZ4003通过除去甲氧基的衍生物，是对NUAK1 / 2酶活性，肿瘤细胞增殖和诱导肿瘤细胞凋亡具有更强抑制作用的最有潜力的化合物。通过结肠直肠SW480异种移植的体内功效评估，9q在体内具有优异的安全性，可以更有效地抑制肿瘤生长，因此被视为进一步研究的合适候选者。