Indoleamine 2,3-Dioxygenase Is the Anticancer Target for a Novel Series of Potent Naphthoquinone-Based Inhibitors
Citations Over Time
Abstract
Indoleamine 2,3-dioxygenase (IDO) is emerging as an important new therapeutic target for the treatment of cancer, chronic viral infections, and other diseases characterized by pathological immune suppression. While small molecule inhibitors of IDO exist, there remains a dearth of high-potency compounds offering <i>in vivo</i> efficacy and clinical translational potential. In this study, we address this gap by defining a new class of naphthoquinone-based IDO inhibitors exemplified by the natural product menadione, which is shown in mouse tumor models to have similar antitumor activity to previously characterized IDO inhibitors. Genetic validation that IDO is the critical <i>in vivo</i> target is demonstrated using IDO-null mice. Elaboration of menadione to a pyranonaphthoquinone has yielded low nanomolar potency inhibitors, including new compounds which are the most potent reported to date (<i>K</i><sub>i</sub> = 61–70 nM). Synthetic accessibility of this class will facilitate preclinical chemical−genetic studies as well as further optimization of pharmacological parameters for clinical translation.
Related Papers
- → 1,4-Naphthoquinone, an intermediate in juglone (5-hydroxy-1,4-naphthoquinone) biosynthesis(1976)31 cited
- → Synthesis of 5,8-Dihydroxy-2-methoxy-1,4-naphthoquinone Derivatives. A Major Naphthoquinone Moiety of Some of Naphthoquinone Antibiotics(1987)18 cited
- → Formation of 5-Hydroxy-3-methoxy-1,4-naphthoquinone and 8-Hydroxy-4-methoxy-1,2-naphthoquinone from Juglone(2012)3 cited
- → A New Method for the Biomimetic Synthesis of 2-Hydroxy-3-Amino-1,4-Naphthoquinone(2013)1 cited
- → ChemInform Abstract: Synthesis of Naphthoquinone Derivatives. Part 4. Synthesis of 5,8‐Dihydroxy‐2‐methoxy‐1,4‐naphthoquinone Derivatives. A Major Naphthoquinone Moiety of Some of Naphthoquinone Antibiotics.(1987)