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.
Guangwei Xu  1 ,  Tianqi Wang  1 ,  Yongtao Li  1 ,  Zhi Huang  1 ,  Xin Wang  1 ,  Jianyu Zheng  2 ,  Shengyong Yang  3 ,  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.
PMID: 29932010 DOI: 10.1080/14756366.2018.1471688
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.
Products