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

Qianming Du; Xi Feng; Yinuo Wang; Xi Xu; Yan Zhang; Xinliang Qu; Zhiyu Li; Jinlei Bian

doi:10.1016/j.ejmech.2019.111629

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. Epub 2019 Aug 18.

Authors

Qianming Du¹, Xi Feng², Yinuo Wang³, Xi Xu², Yan Zhang⁴, Xinliang Qu⁵, Zhiyu Li⁶, Jinlei Bian⁷

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.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Caco-2 Cells
Carcinoma, Non-Small-Cell Lung / drug therapy*
Carcinoma, Non-Small-Cell Lung / metabolism
Carcinoma, Non-Small-Cell Lung / pathology
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
HeLa Cells
Humans
Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors*
Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
Lung Neoplasms / drug therapy*
Lung Neoplasms / metabolism
Lung Neoplasms / pathology
Male
Mice
Mice, Inbred C57BL
Molecular Structure
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / metabolism
Neoplasms, Experimental / pathology
Rats
Structure-Activity Relationship

Substances

Antineoplastic Agents
Enzyme Inhibitors
IDO1 protein, human
Indoleamine-Pyrrole 2,3,-Dioxygenase