Polycomb repressive complex 1 (PRC1) is an essential chromatin-modifying complex that monoubiquitinates histone H2A and is involved in maintaining the repressed chromatin state. Emerging evidence suggests PRC1 activity in various cancers, rationalizing the need for small-molecule inhibitors with well-defined mechanisms of action. Here, we describe the development of compounds that directly bind to RING1B–BMI1, the heterodimeric complex constituting the E3 ligase activity of PRC1. These compounds block the association of RING1B–BMI1 with chromatin and inhibit H2A ubiquitination. Structural studies demonstrate that these inhibitors bind to RING1B by inducing the formation of a hydrophobic pocket in the RING domain. Our PRC1 inhibitor, RB-3, decreases the global level of H2A ubiquitination and induces differentiation in leukemia cell lines and primary acute myeloid leukemia (AML) samples. In summary, we demonstrate that targeting the PRC1 RING domain with small molecules is feasible, and RB-3 represents a valuable chemical tool to study PRC1 biology.

Polycomb 抑制复合物 1 (PRC1) 是一种重要的染色质修饰复合物，可单泛素化组蛋白 H2A，并参与维持抑制的染色质状态。新出现的证据表明 PRC1 在多种癌症中具有活性，合理化了对具有明确作用机制的小分子抑制剂的需求。在这里，我们描述了直接结合 RING1B-BMI1 的化合物的开发，RING1B-BMI1 是构成 PRC1 的 E3 连接酶活性的异二聚体复合物。这些化合物阻断 RING1B-BMI1 与染色质的结合并抑制 H2A 泛素化。结构研究表明，这些抑制剂通过诱导 RING 结构域中疏水口袋的形成来与 RING1B 结合。我们的 PRC1 抑制剂 RB-3 可降低 H2A 泛素化的整体水平并诱导白血病细胞系和原发性急性髓系白血病 (AML) 样本的分化。总之，我们证明用小分子靶向 PRC1 RING 结构域是可行的，并且 RB-3 代表了研究 PRC1 生物学的有价值的化学工具。