CDK-TCIP1 is a bivalent molecule linking CDK9 inhibitor SNS-032 to BCL6 ligand BI3812, activates BCL6-regulated transcription, potently and specifically kills BCL6-overexpressing cells with EC50 of 7.7 nM for SUDHL5 cells.
CDK-TCIP1 shows 55 times greater cytotoxicity than the effect of the CDK9 and BCL6 parental inhibitors.
CDK-TCIP1 is uniquely potent in DLBCL lines dependent on having high levels of BCL6 expression due to oncogenic mutations in the BCL6 gene or its regulatory regions.
CDK-TCIP1 functions by ternary complex formation and relocalization of CDK9 activity to BCL6 on chromatin.
CDK-TCIP1 forms a ternary complex between purified BCL6BTB and CDK9-CycT1 with EC50 of 11 nM, activates BCL6-controlled GFP expression in DLBCL cells, with a comparable EC50 of 58 nM.
CDK-TCIP1 selectively recruit CDK9 and its activity to BCL6-repressed genetic loci.
CDK-TCIP1 significantly increases the expression of pro-apoptotic, BH3 (BCL2 homology 3)-domain containing, BCL6-target genes in mRNA, including BBC3 (BCL2-interacting protein 3; also called PUMA for p53-upregulated modulator of apoptosis) and PMAIP1 (also called NOXA), as well as the cell cycle arrest gene CDKN1B (p27).