2. Academic Validation
  3. Discovery of 5-(pyridin-3-yl)-1H-indole-4,7-diones as indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors

Discovery of 5-(pyridin-3-yl)-1H-indole-4,7-diones as indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors

  • Bioorg Med Chem Lett. 2020 Feb 15;30(4):126901. doi: 10.1016/j.bmcl.2019.126901.
Kai-Min Kong 1,  Jia-Wei Zhang 1,  Bing-Zhi Liu 1,  Guang-Rong Meng 1,  Qian Zhang 2
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 2 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address: [email protected].
PMID: 31882299 DOI: 10.1016/j.bmcl.2019.126901
Abstract

Early studies demonstrated that over expression of indoleamine 2,3-dioxygenase (IDO1) in tumor microenvironment results in tumor immune escape. Herein, in order to simplify the structure of two kinds of IDO1 inhibitors from marine alkaloid, Exiguamine A and Tsitsikammamines, we designed, synthesized a series of 1H-indole-4,7-dione derivatives and evaluated their inhibitory activity in IDO1 enzyme and in IFN-γ stimulated Hela cells in vitro. The structure-activity relationship demonstrated that 5-(pyridin-3-yl)-1H-indole-4,7-dione is a promising scaffold for IDO1 inhibitors and most compounds with this core showed moderate inhibition potency at micromole level. Our further enzyme kinetics experiments reveal that these new developed compounds might act as reversible competitive inhibitors of IDO1.

Keywords

1H-indole-4,7-diones; Cancer immunotherapy; Indoleamine 2,3-dioxygenase 1; Marine alkaloid; Reversible competitive inhibitor.

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