Development of PRC1 Inhibitors Employing Fragment-Based Approach and NMR-Guided Optimization.

Polycomb Repressive Complex 1 (PRC1) is associated with transcriptional silencing, and its dysregulation plays an important role in various cancers. Well-characterized PRC1 inhibitors can facilitate the exploration of PRC1 inhibition as therapeutic agents. By employing an NMR-based fragment screening approach, we have previously identified a very weak millimolar ligand , which directly binds to RING1B-BMI1. Then, we reported a low-micromolar PRC1 inhibitor, , which is active in leukemic cells, showing inhibition of H2A ubiquitylation and modulation of target genes. Here, we describe details of the optimization campaign of into potent PRC1 inhibitors by guiding the SAR employing two NMR approaches and a probe-based biochemical assay. These efforts, combined with medicinal chemistry optimization, resulted in the development of and slightly improved . We have demonstrated that binds to both RING1A and RING1B proteins and inhibits the activity of RING1B-BMI1 and RING1B-PCGF1, representing both canonical and noncanonical PRC1 complexes.