Tumors benefit greatly from a local inflammatory environment but must escape immune-mediated rejection. Indoleamine 2.3-dioxygenase (IDO) suppresses T cell activation by catalyzing the breakdown of the essential amino acid tryptophan. Increased IDO activity has been associated with a broad spectrum of cancers and is implicated in the pathophysiological process of tumoral immune escape. Using the small molecule IDO inhibitory compound 1-methyl-tryptophan (1MT) in transgenic MMTV-Neu mice, we have previously shown that inhibiting the IDO enzyme can leverage the efficacy of cytotoxic chemotherapy in this autochthonous breast cancer model. Further preclinical evaluation of 1MT has indicated that the D and L stereoisomers show marked cell type variation in their ability to inhibit IDO activity with clear biological consequences. Here we report on a novel structural class IDO inhibitory compounds based on the core lead structure brassinin. Brassinin is a naturally occurring, indole-containing phytoalexin with chemopreventative activity in preclinical models. Identification of brassinin as a competitive IDO inhibitor led us to develop a pharmacologic formulation of brassinin, along with the more potent derivative 5-Br-brassinin, that achieves sufficient systemic exposure to evaluate these compounds for therapeutic efficacy in mice. We will present data in both autochthonous and isograft tumor models demonstrating the anti-tumor properties of these compounds. Follow-up studies in nude mice and IDO knockout mice directly support inhibition of both T cell function and IDO activity as necessary to the mechanism of action. We will also present data in a mouse carcinogenesis model evaluating the relevance of IDO inhibition to the ability of brassinin to act as a chemopreventative agent. Derivatization around the brassinin core structure has led to the identification of more potent compounds, providing the basis for structure activity relationship analysis that will inform future IDO inhibitor development.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA