Li Yingjun, Pasunooti Kalyan Kumar, Peng Hanjing, Li Ruo-Jing, Shi Wei Q, Liu Wukun, Cheng Zhiqiang, Head Sarah A, Liu Jun O
Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States.
Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States.
ACS Med Chem Lett. 2020 Apr 8;11(6):1111-1117. doi: 10.1021/acsmedchemlett.9b00438. eCollection 2020 Jun 11.
Itraconazole, a widely used antifungal drug, was found to possess antiangiogenic activity and is currently undergoing multiple clinical trials for the treatment of different types of cancer. However, it suffers from extremely low solubility and strong interactions with many drugs through inhibition of CYP3A4, limiting its potential as a new antiangiogenic and anticancer drug. To address these issues, a series of analogs in which the phenyl group is replaced with pyridine or fluorine-substituted benzene was synthesized. Among them the pyridine- and tetrazole-containing compound has significantly improved solubility and reduced CYP3A4 inhibition compared to itraconazole. Similar to itraconazole, compound inhibited the AMPK/mTOR signaling axis and the glycosylation of VEGFR2. It also induced cholesterol accumulation in the endolysosome and demonstrated binding to the sterol-sensing domain of NPC1 in a simulation study. These results suggested that compound may serve as an attractive candidate for the development of a new generation of antiangiogenic drug.
伊曲康唑是一种广泛使用的抗真菌药物，被发现具有抗血管生成活性，目前正在进行多项治疗不同类型癌症的临床试验。然而，它的溶解度极低，并且通过抑制CYP3A4与许多药物存在强烈相互作用，这限制了其作为新型抗血管生成和抗癌药物的潜力。为了解决这些问题，合成了一系列将苯基替换为吡啶或氟代苯的类似物。其中，含吡啶和四唑的化合物与伊曲康唑相比，溶解度显著提高，对CYP3A4的抑制作用降低。与伊曲康唑类似，该化合物抑制了AMPK/mTOR信号轴以及VEGFR2的糖基化。在模拟研究中，它还诱导了胆固醇在内溶酶体中的积累，并显示出与NPC1的固醇感应结构域结合。这些结果表明，该化合物可能是开发新一代抗血管生成药物的有吸引力的候选物。
