Hussain Afzal, Jairajpuri Deeba Shamim, Anwar Saleha, Choudhury Arunabh, Hawwal Mohammed F, Firdous Anam, Alajmi Mohamed F, Hassan Md Imtaiyaz
Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Department of Medical Biochemistry, College of Medicine and Health Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain.
Mol Divers. 2025 Jan 22. doi: 10.1007/s11030-025-11104-x.
Apigenin, a dietary flavonoid with notable anti-cancer properties, has emerged as a promising candidate for the treatment of neurodegenerative disorders, particularly Alzheimer's disease (AD). While extensively studied for its ability to modulate key molecular pathways in cancers, apigenin also exerts neuroprotective effects by reducing neuroinflammation, protecting neurons from oxidative stress, and enhancing neuronal survival and synaptic plasticity. This dual functionality makes apigenin an intriguing therapeutic option for diseases like AD, where kinase dysregulation plays a central role. In this study, we focus on Microtubule Affinity-Regulating Kinase 4 (MARK4), a key enzyme implicated in tauopathies associated with AD, as well as in cancer progression. Through in silico analysis, we explore the interaction between apigenin and MARK4, revealing significant structural changes within the kinase domain upon ligand binding. These computational findings were confirmed via experimental assays using purified recombinant MARK4, where apigenin demonstrated potent inhibition with an IC value of 2.39 µM. Fluorescence binding assays further confirmed a strong binding affinity (Ka = 10 M), indicating that apigenin efficiently occupies the MARK4 active site, thereby suppressing its enzymatic activity. These results position apigenin as a potent inhibitor of MARK4, offering a dual therapeutic advantage-both as an anti-cancer agent and as a neuroprotective compound for the potential treatment of AD. This study opens new avenues for the development of apigenin-based therapeutics targeting kinase dysregulation in cancer and neurodegeneration.
芹菜素是一种具有显著抗癌特性的膳食黄酮类化合物，已成为治疗神经退行性疾病，尤其是阿尔茨海默病（AD）的有前景的候选药物。虽然芹菜素因其调节癌症关键分子途径的能力而得到广泛研究，但它还通过减轻神经炎症、保护神经元免受氧化应激以及增强神经元存活和突触可塑性发挥神经保护作用。这种双重功能使芹菜素成为治疗像AD这样激酶失调起核心作用的疾病的一个有趣的治疗选择。在本研究中，我们聚焦于微管亲和力调节激酶4（MARK4），这是一种与AD相关的tau蛋白病以及癌症进展有关的关键酶。通过计算机模拟分析，我们探索了芹菜素与MARK4之间的相互作用，揭示了配体结合后激酶结构域内的显著结构变化。这些计算结果通过使用纯化的重组MARK4的实验测定得到证实，其中芹菜素表现出强效抑制作用，IC值为2.39 μM。荧光结合测定进一步证实了强结合亲和力（Ka = 10 M），表明芹菜素有效地占据了MARK4活性位点，从而抑制其酶活性。这些结果将芹菜素定位为MARK4的强效抑制剂，提供了双重治疗优势——既作为抗癌剂，又作为潜在治疗AD的神经保护化合物。这项研究为开发针对癌症和神经退行性疾病中激酶失调的基于芹菜素的治疗方法开辟了新途径。
