IDO and TDO are strongly implicated as cancer immunotherapy targets by the central role they play in the catabolism of tryptophan to kynurenine, a known immunosuppressive pathway, and their over-expression in a large number of tumor types. However, clinical results from recent trials with selective IDO inhibitors have been modest at best, suggesting IDO inhibition alone is not sufficient to achieve compelling clinical outcomes. Herein, we describe the discovery of novel, potent, and orally bio-available imidazoisoindole based small-molecule dual inhibitors of the human isoform of IDO and TDO. This chemical series was the result of a research collaboration with NewLink Genetics which evolved from GDC-919, an IDO selective clinical candidate. Through modification of the C5 substituent, we were able to identify TDO selective compounds, which was the initial aim of the research collaboration. Next, activity against IDO was gained through further modification of the same element to arrive at potent dual IDO/TDO inhibitors. Finally, through optimization of compound physical properties, potent and orally bio-available dual inhibitors were identified.

Discovery and optimization of imidazoisoindole-based IDO/TDO dual inhibitors

2019 Spring National Meeting

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