During their development tumors acquire the capability to escape immune control. Immune escape is a fundamental trait of cancer, but until recently there was little understanding of how it develops. IDO is an enzyme that we and others have found to drive immune escape in tumors, where IDO is often inappropriately switched on.
In the present project, we are moving forward to develop our discovery that drug-like small molecule inhibitors of the IDO enzyme stimulate the immune system to attack tumors in an animal in a manner that synergistically leverages the responses that can be achieved with chemotherapy or radiotherapy. The combination of a traditional chemotherapeutic agent, cytoxan (CTX), and 1-methyl-tryptophan (1-MT), a known IDO inhibitor, have demonstrated considerable therapeutic potential (see Combo in Figure 1; tumor is imaged with bioluminiscence).
Figure 1: Preliminary mice study
Over the past several years, we have systematically explored and optimized three structural classes of IDO inhibitors through traditional structure-activity relationship studies. These include the dithiocarbamates (Figure 2 and J. Med. Chem. 2006, 49(2), 684-692), the naphthoquinones (Figure 3 and J. Med. Chem. 2008, 51(6), 1706-1718), and the phenyl-imidazoles (Figure 4 and J. Med. Chem. 2008 51(16), 4968-4977).
