# Identification of molecular glues targeting FoxP3 to modulate Treg suppressive function and enhance anti-tumor immunity > **NIH NIH F31** · NORTHWESTERN UNIVERSITY · 2024 · $44,187 ## Abstract Project Summary Cancer remains one of the leading causes of death worldwide despite advances in diagnoses and treatments. Immunomodulatory therapeutics like anti-PD-L1 and anti-PD1 enhance the host immune response against the tumor and have saved countless lives. However, these treatments only work a small fraction of the time. Immunosuppressive T-regulatory cells (Tregs) have come under scrutiny as the ratio of Tregs in the tumor microenvironment can dictate both clinical prognoses and whether a patient responds to immunotherapy treatment. Furthermore, current therapeutics to target Treg suppressive function, directly or indirectly, remain unspecific and transient with an extremely low efficacy. Therefore, new therapeutics need to be developed against Tregs and Treg suppressive function. Forkhead box protein 3 (FoxP3) is a Treg and Treg suppressive function specific target. FoxP3 is not only a lineage defining marker in Tregs, but also the master regulator of Treg differentiation and function. Given the role of FoxP3 as a transcription factor though, FoxP3 is known to be “notoriously undruggable” due to both its nuclear localization and lack of inhibitable binding pocket. Fortunately, our lab and others have shown chemically targeting the ubiquitin proteasome system (UPS) can regulate FoxP3 protein levels, and in turn, modulate Treg suppressive function. Unfortunately, UPS enzymes have wide substrate diversity and broad cell type expression, leading to off-target effects. However, through using small molecule compounds known as “molecular glues,” we can specifically glue FoxP3 with E3 ligases to promote its targeted proteasomal degradation. My preliminary data identifies and characterizes one lead small molecule compound as a FoxP3 degrader. First, using a FoxP3-GFP reporter system, 81 potential hits were identified from 640 small molecule library, which reduced FoxP3. Following a secondary dose-response screen, an additional screen by flow cytometry in human Treg-like MT-2 cells, and resynthesis of four potential lead compounds, one lead compound, termed MG03, was identified. MG03 was found to decrease FoxP3 in MT-2 cells as well as mouse primary Tregs, and my preliminary data suggests that MG03 promotes proteasomal degradation of FoxP3. Thus, the long-term goal of this proposed project is to further develop this lead compound to target Treg suppressive function in the context of cancer. The central hypothesis for this project is that Tregs can be targeted through FoxP3 by small molecular degraders to partially diminish Treg suppressive function and enhance the anti-tumor response. To test this hypothesis, we will address the following aims: Aim 1 will determine efficacy of the lead compound, MG03, in inducing FoxP3 degradation in vitro; Aim 2 will investigate the underlying mechanisms of MG03; and Aim 3 will evaluate efficacy of MG03 on Treg suppressive function in vitro and in vivo. This study will identify the first FoxP3-specific molecu... ## Key facts - **NIH application ID:** 10993888 - **Project number:** 1F31CA287701-01A1 - **Recipient organization:** NORTHWESTERN UNIVERSITY - **Principal Investigator:** Amy Tang - **Activity code:** F31 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $44,187 - **Award type:** 1 - **Project period:** 2024-09-01 → 2026-08-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10993888 ## Citation > US National Institutes of Health, RePORTER application 10993888, Identification of molecular glues targeting FoxP3 to modulate Treg suppressive function and enhance anti-tumor immunity (1F31CA287701-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10993888. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*