RB-322

RB-322 is a potent, cell-permeable next-generation small molecule inhibitor of the Polycomb Repressive Complex 1 (PRC1). It specifically targets the E3 ligase activity of the Ring1A/B-BMI1 heterodimer, which is responsible for the monoubiquitylation of histone H2A at lysine 119 (H2AK119Ub). By inhibiting this epigenetic mark, RB-322 leads to the derepression of PRC1 target genes involved in cell fate and identity. Developed as a follow-up to the first-in-class inhibitor RB-3, RB-322 exists as a mixture of two atropisomers, with RB-322-1 demonstrating superior binding affinity and biochemical potency compared to RB-322-2. In preclinical models of acute myeloid leukemia (AML), RB-322-1 has shown the ability to rapidly reduce cellular H2AK119Ub levels and induce growth arrest, making it a valuable chemical probe for studying PRC1 biology and a potential candidate for further oncological development.