Immune checkpoint therapy has demonstrated durable clinical responses in multiple solid tumor types. Reduced clinical response to checkpoint therapy has been linked to the presence of potent immunosuppressive regulatory T cells (Tregs) within the tumor microenvironment that contribute to tumor immune evasion. The transcription factor Helios (IKZF2) is a marker of highly suppressive Tregs and is required to maintain a stable, suppressive Treg cell phenotype in the inflammatory tumor microenvironment. Depletion of IKZF2 in Tregs results in both loss of suppressive activity and conversion of Tregs into effector-like T cells, leading to anti-tumor immunity. Targeted protein degradation using the endogenous Ubiquitin Proteasome System (UPS) has enabled targeting undruggable proteins, such as IKZF2, that have no known small molecule binding pocket. We have designed small molecules that promote a novel interaction between IKZF2 and the E3 ubiquitin ligase substrate receptor, cereblon, leading to proximity induced protein degradation…