Design and synthesis of indoleamine-2,3-dioxygenase 1 inhibitors
targeting cancer immunotherapy
keywords:
Indoleamine-pyrrole 2,3-dioxygenase (IDO or INDO)
Immune checkpoints
Immune tolerance, or immunological tolerance, or immunotolerance:
cancer immunotherapy
ABSTRACT:
Immune cells create a complex cytokine environment that promotes cancer cell survival, angiogenesis, invasion and metastasis1. To survive in this environment, however, cancer cells expressing recognizable tumor antigens must evolve strategies to thwart immune detection and destruction2. Immune escape is thus a hallmark of cancer progression, but its underlying molecular genetic basis remains poorly understood. The interplay between immune escape and other hallmarks of malignant conversion, such as invasion and metastasis, is similarly obscure. Aggressive and disseminated cancers can be eradicated by an appropriately activated immune system, arguing that overcoming immune escape might have broad therapeutic impact, but this expectation has yet to be realized. Small-molecule drugs are of particular interest because of their relative advantages compared to biological agents in terms of production, delivery and cost. Yet few small molecules for stimulating antitumor immunity have been described.
Tumors are composed of abnormally transformed cell types and tissues that differ from normal tissues in their genetic and epigenetic makeup, metabolism, and immunology. Molecular compounds that modulate the immune response against neoplasms offer promising new strategies to combat cancer. Inhibitors targeting the indoleamine-2,3-dioxygenase 1 enzyme (IDO1) represent one of the most potent therapeutic opportunities to inhibit tumor growth. Herein, we assess the biochemical role of IDO1 in tumor metabolism and immune surveillance, and review current diagnostic and therapeutic approaches that are intended to increase the effectiveness of immunotherapies against highly aggressive and difficult-to-treat IDO-expressing cancers.
