IKZF2 (Helios) is a member of the Ikaros family of zinc finger transcription factors. IKZF2 genetic knockout in mice was shown to destabilize immune-repressive regulatory T-cells and it was hypothesized that selective IKZF2 downregulation might safely enhance immune responses to tumors. Currently there are no therapies that modulate IKZF2 and targeting transcription factors remain challenging. Pomalidomide, an IMiD drug, targets the closely related IKZF1/3 transcription factors through a E3 ligase Cereblon-mediated degradation mechanism. Through a medicinal chemistry effort we developed a new molecular glue degrader that selectivity degrades IKZF2 but not IKZF1/3. The compound selectivity was confirmed by target specific degradation assays and by expression proteomics in Jurkat cells, and its ability to modulate immune cell activity and tumor growth was demonstrated in vitro and in vivo. The compound is currently being investigated in human clinical trials as an immunomodulatory drug.

Discovery and characterization of a first-in-class selective IKZF2 glue degrader for immuno-oncology applications

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.