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  3. A novel small-molecule fatty acid synthase inhibitor with antitumor activity by cell cycle arrest and cell division inhibition

A novel small-molecule fatty acid synthase inhibitor with antitumor activity by cell cycle arrest and cell division inhibition

  • Eur J Med Chem. 2021 Jul 5:219:113407. doi: 10.1016/j.ejmech.2021.113407.
Hongyan Qu 1,  Kai Shan 1,  Chunlei Tang 2,  Guozhen Cui 3,  Guoling Fu 1,  Yumin Qi 1,  Jing Cui 1,  Jiaqi Li 1,  Rong Wang 1,  Ninghan Feng 4,  Yong Q Chen 5
Affiliations

Affiliations

  • 1 Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu Province, 214012, China; School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu Province, 214012, China.
  • 2 School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu Province, 214012, China.
  • 3 Department of Bioengineering, Zhuhai Key Laboratory of Basic and Applied Research in Chinese Medicine, Zhuhai Campus of Zunyi Medical University, Zhuhai, Guangdong Province, 519041, China.
  • 4 Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu Province, 214012, China; Department of Urology, Wuxi No.2 People's Hospital of Nanjing Medical University, Wuxi, Jiangsu Province, 214012, China; Wuxi Clinical College, Nantong University, Wuxi, Jiangsu, China.
  • 5 Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu Province, 214012, China; School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu Province, 214012, China. Electronic address: [email protected].
PMID: 33901805 DOI: 10.1016/j.ejmech.2021.113407
Abstract

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.

Keywords

Fatty acid synthase inhibitor; S-phase arrest; Structure-based virtual screening.

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