A small molecule BCL6 inhibitor effectively suppresses diffuse large B cell lymphoma cells growth

Abstract The B-cell lymphoma 6 (BCL6) transcription factor plays a key role in establishment of germinal center (GC) formation. Diffuse large B cell lymphoma (DLBCL) originates from the GC reaction due to dysregulation of BCL6. Disrupting BCL6 and its corepressors interaction has become the foundation for rationally designing lymphoma therapies. However, BCL6 inhibitors with good activities in vitro and in vivo are rare and there are no clinically approved BCL6 inhibitors. Here, we discovered and developed a novel range of [1,2,4] triazolo[1,5-a] pyrimidine derivatives targeting BCL6/SMRT interaction. The analogue WK692 directly bound BCL6BTB, disrupted BCL6BTB/SMRT interaction and activated the expression of BCL6 downstream genes inside cells, inhibited DLBCL growth and induced apoptosis in vitro, inhibited GC formation, decreased proportion of follicular helper T (Tfh) cells and impaired immunoglobulin affinity maturation. Further studies showed that WK692 inhibited the DLBCL growth without toxic effects in vivo and synergizes with the EZH2 and PRMT5 inhibitors. Our results demonstrated that WK692 as a BCL6 inhibitor may be developed as a novel potential anticancer agent against DLBCL.