Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu Province, 214012, China; School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu Province, 214012, China.
School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu Province, 214012, China.
Eur J Med Chem. 2021 Jul 5;219:113407. doi: 10.1016/j.ejmech.2021.113407. Epub 2021 Apr 20.
Fatty acid synthase (FASN), the key enzyme in de novo lipogenesis, is an attractive therapeutic target for diseases characterized by excessive lipid accumulation. Many FASN inhibitors have failed in the clinical trial phase, largely because of poor solubility and safety. In this study, we generated a novel small-molecule FASN inhibitor by structure-based virtual screening. PFI09, the lead compound, is easy to synthesize, and inhibits the lipid synthesis in OP9 mammalian cell line and Caenorhabditis elegans as well as the proliferation of several cancer cell lines via the blockade of FASN. Mechanistic investigations show that PFI09 induces S-phase arrest, cell division reduction and apoptosis. We also develop a chemically stable analog of PFI09, MFI03, which reduces the proliferation of PC3 tumor cells both in vitro and in vivo, without toxicity to mice. In summary, our data suggest that MFI03 is an effective FASN inhibitor and a promising antineoplastic drug candidate.
脂肪酸合酶（FASN）是从头合成脂质过程中的关键酶，是脂质过度积累特征性疾病的一个有吸引力的治疗靶点。许多 FASN 抑制剂在临床试验阶段失败，主要是由于溶解度和安全性差。在这项研究中，我们通过基于结构的虚拟筛选生成了一种新型小分子 FASN 抑制剂。先导化合物 PFI09 易于合成，通过阻断 FASN 抑制 OP9 哺乳动物细胞系和秀丽隐杆线虫中的脂质合成以及几种癌细胞系的增殖。机制研究表明，PFI09 诱导 S 期停滞、细胞分裂减少和细胞凋亡。我们还开发了 PFI09 的化学稳定类似物 MFI03，它在体外和体内均能减少 PC3 肿瘤细胞的增殖，且对小鼠无毒性。总之，我们的数据表明 MFI03 是一种有效的 FASN 抑制剂和有前途的抗肿瘤药物候选物。
