2. Academic Validation
  3. Discovery of phosphonamidate IDO1 inhibitors for the treatment of non-small cell lung cancer

Discovery of phosphonamidate IDO1 inhibitors for the treatment of non-small cell lung cancer

  • Eur J Med Chem. 2019 Nov 15:182:111629. doi: 10.1016/j.ejmech.2019.111629.
Qianming Du 1,  Xi Feng 2,  Yinuo Wang 3,  Xi Xu 2,  Yan Zhang 4,  Xinliang Qu 5,  Zhiyu Li 6,  Jinlei Bian 7
Affiliations

Affiliations

  • 1 General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, PR China; Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, China; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
  • 2 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
  • 3 Department of Biology, University of California San Diego, La Jolla, CA, 92093, United States.
  • 4 Department of Gastroenterology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210029, PR China.
  • 5 Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210029, PR China.
  • 6 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: zhiyuli@cpu.edu.cn.
  • 7 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: bianjl@cpu.edu.cn.
PMID: 31445231 DOI: 10.1016/j.ejmech.2019.111629
Abstract

Targeting indoleamine 2,3-dioxygenase 1 (IDO1) has been identified as an attractive approach for the development of Cancer Immunotherapy. In this study, a series of phosphonamidate ester containing compounds were designed, synthesized and evaluated for their inhibitory activities against IDO1. Among them, compounds 16, 17, and 26 with good IDO1 inhibitory (HeLa IDO1 IC50 = 10-21 nM, hIDO1 IC50 = 78-121 nM) activities were selected for further investigation and showed good physicochemical properties. Furthermore, based on comparable PK profile and excellent IDO2/TDO inhibitory potency, representative compound 16 was selected for further bio-evaluation and characterized with good efficacy in suppressing lung metastasis (77% inhibition rate) of Lewis cells in vivo. Thus, compound 16 could be a potential and efficacious agent for further evaluation.

Keywords

Epacadostat; IDO1 inhibitors; IDO2; Phosphonamidate ester; TDO.

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