Over the past decade, the field of immuno-oncology has sought to diversify immunotherapeutics beyond monoclonal antibody-derived checkpoint inhibitors and exploit mechanistic pathways capable of being perturbed by small molecules. Two targets of interest that emerged during these pursuits were indoleamine 2,3-dioxygenase 1 (IDO1) and stimulator of interferon genes (STING). IDO1, which catalyzes tryptophan metabolism, leads to depletion of tryptophan and accumulation of kynurenine via the formation of N-formylkynurenine. In the context of the tumor microenvironment, this can lead to suppressed proliferation, anergy, and apoptosis of T-effector cells as well as support formation of T-regulatory cells. STING, which is indirectly activated by cytosolic DNA via cyclic dinucleotides (CDNs), is a key component of the innate DNA-sensing immune pathway. Binding of CDNs to STING leads to downstream activation of transcription factors IRF-3 and NF-kB which can subsequently lead to expression of proinflammatory type-I IFNs, TNF, and IL-6. Importantly, STING activation has been implicated in priming CD8+ T cells to recognize and attack tumors. This presentation will focus on medicinal chemistry efforts to optimize a heme-displacing class of IDO1 inhibitors and the identification of a novel class of non-CDN derived STING agonists with cross-species activity. Vignettes will include bioisosteres and conformational analysis in drug-design, mechanistic studies, and chemotype hybridization.

Exploring pathways in immuno-oncology: Discovery of IDO1 inhibitors and STING agonists

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.