Abstract 1111: Identification of selective IKZF2 degraders that reprogram suppressive regulatory T cells in solid tumors

Abstract Targeted protein degradation (TPD) using the endogenous Ubiquitin Proteasome System (UPS) is a rapidly growing drug discovery strategy to eliminate pathogenic proteins. Molecular glues are small molecules that promote a novel interaction between a protein of interest with an E3 ubiquitin ligase leading to proximity induced protein degradation. This has enabled targeting undruggable proteins, such as the zinc-finger transcription factor Helios (IKZF2), that have no known small molecule binding pocket. Despite recent clinical breakthroughs in checkpoint blockade in treating solid tumors, suppression of the antitumor immune response in the tumor microenvironment (TME) is a major obstacle to tumor regression. Regulatory T cells (Tregs) in the TME are potent immunosuppressive cells that promote progression of cancer. IKZF2 has been shown to be a marker of highly suppressive Treg cells and is critical for maintaining the anergic and suppressive phenotype in the highly inflammatory tumor microenvironment. Genetic depletion of IKZF2 in Treg cells results in both loss of suppressive activity and conversion of Tregs into T effector cells, leading to enhanced anti-tumor immunity. Collectively, these findings support that an IKZF2-specific degrader could be beneficial in enhancing the efficacy of current immunotherapies. Here we report our efforts leading to the development of a series of potent and selective IKZF2 degraders for the treatment of cancer. Our lead compound, PLX-4107, is a novel molecular glue that was optimized to be a highly selective, deep, and rapid IKZF2 degrader via the redirection of the E3 substrate receptor, cereblon. Proteome-wide analysis demonstrated that PLX-4107 depletes IKZF2 protein levels without degrading other known cereblon neo-substrates. PLX-4107 mediated degradation of IKZF2 resulted in conversion of highly suppressive Tregs into T effector cells, coupled with an increased expression of the effector cytokines IL2 and IFNγ. Oral administration of PLX-4107 to cynomolgus monkeys caused rapid, complete, and prolonged degradation of IKZF2 in Tregs, indicative of the catalytic nature of degraders where sustained pharmacodynamic response is observed well beyond plasma drug exposure levels. These preliminary data provide a strong rationale for developing small molecule therapeutics that target the undruggable IKZF2 transcription factor with the potential to enhance the efficacy of immune checkpoint therapy. Citation Format: Peggy A. Thompson, Pengyu Yang, Xiaoming Li, Stephen Chien, Mary E. Spalding, Alejandro Dearie, Elizabeth Daniele, Linette Yang, E Adam Kallel, Aleksandar Jamborcic, Julia Toth, Gregory Parker, Simon Bailey. Identification of selective IKZF2 degraders that reprogram suppressive regulatory T cells in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1111.