Small molecule IDO inhibitors
A mechanism of vascular protection as a potential treatment for cancer therapies
Reduced immune suppression caused by tumours
Small molecule inhibitors of IDO-1 could be used as a combination or adjunct therapy with chemotherapy, radiotherapy or especially with immunotherapy. Given the inhibitors act to reduce immune suppression caused by tumours, these can be applied to a broad range of cancers.
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Indoleamine-2,3-dioxygenase-1 (IDO-1) is an intracellular enzyme normally expressed in immune cells (such as dendritic cells and macrophages) and is responsible for the catalytic conversion of the essential amino acid tryptophan to various species of kynurenine. A decrease in released tryptophan and the concomitant increase in kynurenines result in immune suppression through the activation of Treg cells and reduced Teffector cell activation. Critically, the enzyme is highly expressed by a broad range of tumours, suppressing the local immune system and thereby avoiding their detection and elimination by immune cells. Moreover, high IDO-1 expression has been shown to be correlated with poor patient outcome for all major classes of solid and haematological malignancies that have been investigated (lung, melanoma, glioma, colorectal, pancreatic, hepatic, renal, prostate, breast, ovarian, cervical, endometrial, and the haematological malignancies; chronic lymphocytic leukaemia and B-cell lymphomas). Experimental knock-down of IDO-1 gene expression in a mouse melanoma line blocked its ability to grow when implanted into mice, further validating the IDO-1 enzyme as a target for cancer intervention.An Auckland Cancer Society Research Centre (ACSRC) research team has undertaken a novel drug discovery effort to identify and develop novel small molecule IDO-1 inhibitors.
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