School of Medical Sciences


Restoring tumour immunity with inhibitors of IDO1

STG IDO1 Interaction with Cells

Cancers have evolved a number of mechanisms to suppress the immune system in order to escape elimination. These mechanisms of tumour mediated immune suppression inactivate not only the endogenous immunity of the patient; they also limit the efficacy of administered vaccines and T cell immunotherapies. Small molecule inhibitors of the immune suppressive protein indoleamine 2,3-dioxygenase (IDO1), the rate-limiting enzyme in the catabolism of the essential amino acid tryptophan, has emerged as one of the more promising approaches to restoring tumour immunity to cancer patients. Silencing of the IDO1 gene in animal models resulted in slower rates of tumour development and growth, validating IDO1 as an exciting new target for cancer therapy.

 

Working closely with the medicinal chemistry group at the ACSRC, we have discovered a new class of IDO1 inhibitors that binds in active site with different kinetics and mode of action compared to known IDO1 inhibitors. These novel molecules are being used to probe the intermolecular interactions involved in ligand binding to the active site of the IDO1 enzyme and as tools to dissect the effect of IDO1 expression by tumours on the host T-cell immunobiology. The efficacy of these IDO1 inhibitors as potential anti-cancer agents are being investigated in combination with immunotherapies in preclinical models of glioma, melanoma and lung cancers.  

References


Fung S-PS, Wang H, Tomek P, Squire CJ, Flanagan JU, Palmer BD, Bridewell DJA, Tijono SM, Jamie JF, Ching L-M. Discovery and characterization of hydrazine derivatives as inhibitors of the immune inhibitory enzyme, indoleamine 2,3-dioxygenase 1 (IDO1). Bioorg Med Chem, 21, 7595-7603, 2013.

Tomek P, Palmer BD, Flanagan JU, Fung S-PS, Bridewell BD, Jamie JF, Ching L-M. Formation of an N-formylkynurenine-derived fluorophore and its use for measuring indoleamine 2,3-dioxygenase 1 activity. Anal Bioanal Chem , 405, 2515-2524, 2013.