Novel Small Molecules Target BCL6 To Suppress Diffuse Large B Cell Lymphoma

Diffuse large B cell lymphoma(DLBCL)which arises from the germinal center(GC)exhibits highly aggressive.The clinical classification of DLBCL is complex,which exhibits highly heterogeneous in histomorphology,molecular biology,genetics,clinical manifestations,efficacy and prognosis.CD20 monoclonal antibody combined with conventional chemotherapy regimen(CHOP)is the standard therapy of DLBCL.Although some patients can be cured after treatment,about 40% of patients still fail to receive treatment due to disease recurrence or primary drug resistance.For relapsed/refractory DLBCL,there is still a lack of effective clinical treatment.Therefore,it is an urgent problem to find new targeted therapies according to the pathogenesis of DLBCL.Studies have shown that the occurrence and development of DLBCL is closely related to the abnormal expression of B cell lymphoma 6(BCL6).BCL6 is a transcriptional repressor which is crucial for GC development.Constitutive expression of BCL6 in GC is the direct reason for driving DLBCL.Studies on the structure and function of BCL6 protein have found that BCL6 is a potential drug target and targeting BCL6 is a feasible approach to treat DLBCL.Up to now,there is no effective BCL6 inhibitor with favorable activity in vivo and in vitro,and the clinical research in this field is also in a blank.To screen and identify novel BCL6 inhibitors with better activity both in vitro and in vivo,a luciferase reporter assay,which allowed to assess of BCL6 mediated transcriptional repression activity,and a HTRF high throughput screening model evaluating disruption of BCL6-SMRT interaction were constructed.We screened more than five hundred of small molecule compounds and two novel small molecule compounds WK500 B and WK692 with completely different structures were identified.At the molecular level,WK500 B and WK692 directly bound to the BTB domain of BCL6,and blocked the interaction between BCL6 and SMRT.At the cellular level,WK500 B and WK692 reactivated BCL6 target genes,inhibited DLBCL cells proliferation and induced apoptosis.In animals,WK500 B and WK692 significantly inhibited GC formation and DLBCL tumor growth in mice without toxic and side effects.Preliminary mechanism studies have shown that WK500 B and WK692 disrupted the transcription complex formation by interfering with BCL6 recruitment of SMRT,thus inhibiting the transcriptional activity of BCL6.WK500 B and WK692 exerted better efficacy than the positive compound FX1 in all evaluative system.More importantly,WK500 B had favorable metabolic stability and pharmacokinetic characteristics,and WK692 blocked the interaction between BCL6 and SMRT at the concentration of nanomole and had better cell selectivity.In summary,WK500 B and WK692 are novel and highly effective BCL6 inhibitors with better activity both in vitro and in vivo,and they are expected to be candidate compounds for the treatment of DLBCL.