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.

MRG15 activates histone methyltransferase activity of ASH1L by recruiting it to the nucleosomes.

ASH1L is a histone methyltransferase that regulates gene expression through methylation of histone H3 on lysine K36. While the catalytic SET domain of ASH1L has low intrinsic activity, several studies found that it can be vastly enhanced by the interaction with MRG15 protein and proposed allosteric mechanism of releasing its autoinhibited conformation. Here, we found that full-length MRG15, but not the MRG domain alone, can enhance the activity of the ASH1L SET domain.

Molecular investigation of the tandem Tudor domain and plant homeodomain histone binding domains of the epigenetic regulator UHRF2.

Ubiquitin-like containing PHD and ring finger (UHRF)1 and UHRF2 are multidomain epigenetic proteins that play a critical role in bridging crosstalk between histone modifications and DNA methylation. Both proteins contain two histone reader domains, called tandem Tudor domain (TTD) and plant homeodomain (PHD), which read the modification status on histone H3 to regulate DNA methylation and gene expression. To shed light on the mechanism of histone binding by UHRF2, we have undergone a detailed molecular investigation with the TTD, PHD and TTD-PHD domains and compared the binding activity to its UHRF1 counterpart.

Development of potent dimeric inhibitors of GAS41 YEATS domain.

GAS41 is an emerging oncogene overexpressed and implicated in multiple cancers, including non-small cell lung cancer (NSCLC). GAS41 is a dimeric protein that contains the YEATS domain, which is involved in the recognition of lysine-acylated histones. Here, we report the development of GAS41 YEATS inhibitors by employing a fragment-based screening approach.

Small-molecule inhibitors targeting Polycomb repressive complex 1 RING domain.

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.

Identification of Thiourea-Based Inhibitors of the B-Cell Lymphoma 6 BTB Domain via NMR-Based Fragment Screening and Computer-Aided Drug Design.

Protein-protein interactions (PPI) between the transcriptional repressor B-cell lymphoma 6 (BCL6) BTB domain (BCL6) and its corepressors have emerged as a promising target for anticancer therapeutics. However, identification of potent, drug-like inhibitors of BCL6 has remained challenging. Using NMR-based screening of a library of fragment-like small molecules, we have identified a thiourea compound (7CC5) that binds to BCL6.