A highly potent and selective inhibitor Roxyl-WL targeting IDO1 promotes immune response against melanoma

Guangwei Xu; Tianqi Wang; Yongtao Li; Zhi Huang; Xin Wang; Jianyu Zheng; Shengyong Yang; Yan Fan; Rong Xiang

doi:10.1080/14756366.2018.1471688

A highly potent and selective inhibitor Roxyl-WL targeting IDO1 promotes immune response against melanoma

J Enzyme Inhib Med Chem. 2018 Dec;33(1):1089-1094. doi: 10.1080/14756366.2018.1471688.

Authors

Guangwei Xu¹, Tianqi Wang¹, Yongtao Li¹, Zhi Huang¹, Xin Wang¹, Jianyu Zheng², Shengyong Yang³, Yan Fan^{1

4

5}, Rong Xiang^{1

4

5}

Affiliations

¹ a Department of Medicinal Chemistry, School of Medicine , Nankai University , Tianjin , China.
² b State Key Laboratory and Institute of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering , Nankai University , Tianjin , China.
³ c State Key Laboratory of Biotherapy and Cancer Center , West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy , Chengdu , China.
⁴ d State Key Laboratory of Medicinal Chemical Biology , Tianjin , China.
⁵ e 2011 Project Collaborative Innovation Center for Biotherapy of Ministry of Education, Tianjin , China.

Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) activity links to immune escape of cancers. Inhibition of IDO1 provides a new approach for cancer treatment. Most clinical IDO1 drugs show marginal efficacy as single agents. On basis of molecular docking and pharmacophore modelling, a novel inhibitor Roxyl-WL was discovered with a half maximal inhibitory concentration (IC50) value of 1 nM against IDO1 and 10-100-fold increased potent activity compared with IDO1 drugs in clinical trials. Roxyl-WL displayed excellent kinase spectrum selectivity with no activity out of the 337 protein kinases. In vitro, Roxyl-WL effectively augmented the proliferation of T cells and reduced the number of regulatory T cell (Tregs).When administered to melanoma (B16F10) tumor-bearing mice orally, Roxyl-WL significantly suppressed tumor growth and induced immune response.

Keywords: IDO1; immunotherapy; inhibitor; melanoma.

MeSH terms

Animals
CD4-Positive T-Lymphocytes / drug effects
CD4-Positive T-Lymphocytes / immunology
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Female
Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors*
Indoleamine-Pyrrole 2,3,-Dioxygenase / immunology
Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
Melanoma / drug therapy*
Melanoma / immunology
Melanoma / metabolism
Mice
Mice, Inbred C57BL
Molecular Docking Simulation
Molecular Structure
Structure-Activity Relationship

Substances

Enzyme Inhibitors
IDO1 protein, mouse
Indoleamine-Pyrrole 2,3,-Dioxygenase

Grants and funding

This work was supported by the Project of Science and Technology Assistance in Developing Countries (KY201501006), National Natural Science Foundation of China (81470354), Natural Science Foundation of Tianjin (17JCQNJC13500), and the State Key Laboratory of Medicinal Chemical Biology (2018004).