A patent review of IDO1 inhibitors for cancer

ABSTRACT

Introduction: Indoleamine 2,3-dioxygenase 1 (IDO1) is overexpressed by cancer cells and the antigen presenting dendritic cells in the tumor microenvironment (TME). Activation of IDO1 depletes tryptophan and produces kynurenine, which induces T cell anergy and suppresses tumor control by the immune system. When combined with an immune checkpoint inhibitor, IDO1 inhibitors have shown promising anticancer activity in preclinical tumor models as well as in early stage clinical trials.

Areas covered: IDO1 inhibitors disclosed in the patent literature from 2013-2017 are categorized, when applicable, according to their structural similarity to the clinical development candidates indoximod and PF-06840003, navoximod, epacadostat, KHK2455 and aryl-1,2-diamines, and BMS-986205 among others, respectively. Representative structures and their IDO1 inhibitory activity are presented to highlight the novelty and activity. Finally, the reported cocrystal structures were analyzed to provide insights for inhibitor-enzyme interactions and guidance for the design and discovery of next generation inhibitors.

Expert opinion: This review demonstrates that the structural diversity of new IDO1 inhibitors could be expanded via a number of approaches.

KEYWORDS:

• Arylhydrocarbon receptor
• IDO1 inhibitors
• immune escape
• cancer immunotherapy
• kynurenine pathway

Article highlights

• IDO1 is a promising intracellular drug target for the development of cell permeable small molecule cancer immunotherapies.

• Interest in the development of IDO1 inhibitors has increased dramatically as evidenced by the large number of patent applications during 2013-2017.

• Most of the patented IDO1 inhibitors belong to 4 chemical classes: fused [5,6]heteroaromatics (PF-06840003), 4-phenylimidazoles (navoximod), hydroxyamidines (epacadostat), and aryl-1,2-diamines (KHK2455).

• Protein crystallographic studies indicate a flexible catalytic domain and distinctive binding mode unique to the chemical structure of the bound IDO1 inhibitor.

• Opportunities exist to expand the structural diversity of next generation inhibitors.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This research is partially supported by funding for the Center for Drug Discovery and Translational Research at Beth Israel Deaconess Medical Center/Department of Surgery (LS).