Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
School of Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan.
J Enzyme Inhib Med Chem. 2023 Dec;38(1):2166039. doi: 10.1080/14756366.2023.2166039.
Inhibiting a specific target in cancer cells and reducing unwanted side effects has become a promising strategy in pancreatic cancer treatment. MAP4K4 is associated with pancreatic cancer development and correlates with poor clinical outcomes. By phosphorylating MKK4, proteins associated with cell apoptosis and survival are translated. Therefore, inhibiting MAP4K4 activity in pancreatic tumours is a new therapeutic strategy. Herein, we performed a structure-based virtual screening to identify MAP4K4 inhibitors and discovered the compound F389-0746 with a potent inhibition (IC 120.7 nM). The results of kinase profiling revealed that F389-0746 was highly selective to MAP4K4 and less likely to cause side effects. Results of in vitro experiments showed that F389-0746 significantly suppressed cancer cell growth and viability. Results of in vivo experiments showed that F389-0746 displayed comparable tumour growth inhibition with the group treated with gemcitabine. These findings suggest that F389-0746 has promising potential to be further developed as a novel pancreatic cancer treatment.
在癌细胞中抑制特定靶点并减少不必要的副作用已成为治疗胰腺癌的一种有前途的策略。MAP4K4 与胰腺癌的发展有关，并与不良的临床结局相关。通过磷酸化 MKK4，与细胞凋亡和存活相关的蛋白质被翻译。因此，抑制胰腺肿瘤中的 MAP4K4 活性是一种新的治疗策略。在此，我们进行了基于结构的虚拟筛选，以鉴定 MAP4K4 抑制剂，并发现了具有强大抑制作用（IC 120.7 nM）的化合物 F389-0746。激酶谱分析的结果表明，F389-0746 对 MAP4K4 具有高度选择性，不太可能引起副作用。体外实验结果表明，F389-0746 显著抑制癌细胞的生长和活力。体内实验结果表明，F389-0746 与用吉西他滨治疗的组相比显示出相当的肿瘤生长抑制作用。这些发现表明，F389-0746 具有很大的潜力，可以进一步开发为治疗胰腺癌的新型药物。
