Identification and development of a small molecule degrader targeting FoxP3 to enhance the anti-tumor immune response 9164

Abstract Description Forkhead box protein 3 (FoxP3) is the master transcription factor of T regulatory cells (Tregs), and FoxP3 is essential for Treg differentiation and lineage stability as well as Treg immunosuppressive function. Due to its nature as a transcription factor, FoxP3 has been notoriously difficult to pharmacologically target. Here, we report the first small molecule degrader, termed FD03, which can promote proteasomal degradation of FoxP3 to decrease Treg suppressive function. We first identified FD03 by screening a targeted library consisting of small electrophilic compounds. Next, we elucidated that FD03 degrades FoxP3 in part through E3 ligase, STUB1 (CHIP). Finally, we show that FD03 treatment in Tregs in vitro reduces their suppressive capabilities while in vivo FD03 treatment in tumor-bearing mice can significantly reduce tumor burden. This study provides a framework and proof-of-concept for future development of small molecule degraders to target FoxP3 directly to decrease Treg immunosuppression and boost anti-tumor immunity. Funding Sources Supported by NIH/NCI 1F31CA287701-01A1; 1T32GM149439-01; T32 GM15538-10 Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)