Discovery of Tricyclic Oxazinoquinolinone-Based BCL6 PROTAC Degraders with Potent Activity Against Diffuse Large B-Cell Lymphoma

Abstract B-cell lymphoma 6 (BCL6) is a key transcriptional repressor involved in the pathogenesis of diffuse large B-cell lymphoma (DLBCL). In this study, scaffold hopping of BI-3802 led to compound 1, a new tricyclic BCL6-targeting ligand. Further optimization of linker architecture and CRBN-recruiting motifs led to compound 15, a potent BCL6 PROTAC degrader, which induced rapid and efficient BCL6 degradation in OCI-LY1 cells (DC50 = 5.32 nM) and displayed potent antiproliferative activity in BCL6-dependent DLBCL cells (IC50 = 3.2 nM). BCL6 degradation was CRBN- and proteasome-dependent and was accompanied by G1-phase arrest and increased p21 and p27 expression. Oral administration of 15 inhibited tumor growth in an OCI-LY1 xenograft model (TGI = 84% at 20 mg/kg) and reduced tumor BCL6 and Ki67 levels without appreciable body-weight loss or overt major-organ histopathology. Overall, compound 15 represents a promising BCL6 PROTAC degrader for DLBCL.