Structure-based discovery of sulfamoyl-ethyl-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidine amides and sulfonamides as potent B-Cell Lymphoma 6 (BCL6)-BTB inhibitors.

Diffuse Large B-Cell Lymphoma (DLBCL) is one of the most aggressive forms of lymphoid malignancies. About 40 % of patients eventually relapse and succumb to the disease within 5 years after diagnosis, underscoring the need for new treatment modalities. B-Cell Lymphoma 6 protein (BCL6) is a repressive transcription factor that is dysregulated in about 40 % of DLBCLs. As a rationale for pursuing BCL6 as a drug target, disrupting complexes between this protein and its co-repressors is thought to mitigate the downstream oncogenic effects of this pathway. However, drugging transcription factors presents a formidable undertaking since targeting protein-protein interactions has historically been challenging. In this study, we used X-ray structures of BCL6-SMRT (a silencing mediator for retinoid or thyroid-hormone receptors, also known as the nuclear receptor co-repressor 2, NCOR2) peptide and compound 79-6 to conduct a virtual screen of a library of 5.2 million compounds. Through this exercise, we identified the pyrrolopyridone 3 as a viable hit, which in turn led to the identification of pyrrolopyrimidone lead compound 4. The X-ray crystal structure of 4 bound to the BTB (Broad-Complex, Tramtrack, and Bric à brac) domain of BCL6 revealed a large back pocket as well as a left-hand channel adjacent to the ligand that could be leveraged to optimize these compounds. Sulfonamide side chains were therefore introduced to target this space, leading to compounds 11d and 11e having sub-micromolar binding to the BTB domain of BCL6.