Discovery of PLX-4107, a Selective IKZF2 Molecular Glue Degrader, That Modulates Suppressive Regulatory T Cells and Demonstrates Anti-tumor Activity
Immune checkpoint inhibitors (CPI) have significantly advanced cancer treatment; nevertheless, responses are limited to patient subsets, thereby necessitating additional treatment strategies. Regulatory T-cells (Tregs) are a specialized population of CD4+ T-cells that maintain normal immune tolerance and homeostasis; however, in the tumor microenvironment (TME), Tregs are potent immunosuppressive cells that promote tumor immune evasion and reduced clinical response to CPI. The transcription factor IKZF2 is a marker of highly suppressive Tregs and is required to maintain a stable, suppressive Treg cell phenotype in the inflammatory TME. Depletion of IKZF2 reprograms suppressive Tregs into effector-like T-cells leading to anti-tumor immunity, but targeting transcription factors has been challenging due to the lack of defined structures and binding pockets. Protein degradation using the endogenous Ubiquitin Proteasome System (UPS) has enabled accessing undruggable proteins, such as IKZF2, through chemically induced proximity that promotes degradation…