Discovery of a potent and orally bioavailable Cereblon (CRBN)-Mediated ligand directed degrader (LDD) of B cell lymphoma 6 Protein (BCL6)

The B cell lymphoma 6 protein (BCL6) functions as a transcriptional repressor of genes involved in cell cycle, DNA damage repair and pro-apoptosis pathways critical to antibody affinity maturation by B cells within the germinal centers of the lymphatic system. Elevation of BCL6 expression, through genetic aberrations or perturbations to its post-translational regulation, is well established as one of several key oncogenic drivers that contribute to the development of B cell lymphomas. In this context, a degrader approach specific to BCL6 will likely bring significant therapeutic benefit to a large number of lymphoma patients. We explored the use of heterobifunctional protein degraders, also known as Ligand Directed Degraders (LDDs), comprised of a BCL6 binding moiety linked to a cereblon (CRBN) binding moiety to target BCL6 for CRBN-mediated degradation. Herein, we describe the discovery and lead optimization effort that resulted in a potent, selective, and orally efficacious BCL6-LDD.