NR-V04

NR-V04 is a first-of-its-kind proteolysis-targeting chimera (PROTAC) designed to induce the degradation of the nuclear receptor subfamily 4 group A member 1 (NR4A1). Developed by researchers at the University of Florida in collaboration with the University of Copenhagen and the University of Texas Health Science Center at San Antonio, NR-V04 consists of a celastrol-based warhead that binds NR4A1 and a von Hippel-Lindau (VHL) ligand that recruits the E3 ubiquitin ligase. This recruitment leads to the ubiquitination and subsequent proteasomal degradation of NR4A1, a transcription factor known to promote cancer aggressiveness and maintain an immunosuppressive tumor microenvironment (TME). By eliminating NR4A1, NR-V04 modulates the TME by inducing tumor-infiltrating B cells, reducing monocytic myeloid-derived suppressor cells (m-MDSCs) and regulatory T cells (Tregs), and activating CD8+ effector T cells. Preclinical studies have demonstrated that NR-V04 effectively inhibits tumor growth in melanoma and colorectal cancer models with a favorable safety profile.