BMS Symposium: Emily Cherney and Thomas Maimone

Dr. Emily Cherney: Exploring Pathways in Immuno-oncology With Small Molecules: IDO Inhibitors, STING Agonists, and Helios Degraders
Over the past decade, the field of immuno-oncology has looked to diversify beyond antibody-derived checkpoint inhibitors and exploit mechanistic pathways capable of being perturbed by small molecules Targetinclude indoleamine 2,3-dioxygenase 1 (IDO1), stimulator of interferon genes (STING), and Helios (IKZF2). IDO1, which catalyzes tryptophan metabolism, leads to suppressed proliferation, anergy, and apoptosis of T-effector cells and supports the formation of T-regulatory (Treg) cells. STING, which is indirectly activated by cytosolic DNA via cyclic dinucleotides (CDNs), is a key component of the innate DNA-sensing immune pathway. STING activation has been implicated in priming CD8+ T cells to recognize and attack tumors. Helios is a zinc finger transcription factor attributed to the immunosuppressive effects of Treg cells. Helios degradation modulates Treg cells by transcriptionally reprogramming function towards a more destabilized, inflammatory state. This presentation will focus on medicinal chemistry efforts to optimize a heme-displacing class of IDO1 inhibitors, identify a non-CDN derived STING agonist with cross-species activity, and discover a highly selective CELMoDTM degrader of Helios. Through the lens of these discovery stories, strategies to navigate real-world challenges in medicinal chemistry will be explored. Topics will include bioisosteres, prodrugs, conformational analysis, chemotype hybridization, pan-assay interference compounds (PAINS), neosubstrate selectivity, and mechanistic characterization.

Professor Thomas Maimone: TBA