Borrowing Transcriptional Kinases to Activate Apoptosis [RNA-seq]

Protein kinases are disease drivers whose therapeutic targeting traditionally centers on inhibition of enzymatic activity. Here chemically induced proximity is leveraged to convert kinase inhibitors into context-specific activators of therapeutic genes. Bivalent molecules that link ligands of the transcription factor B-cell lymphoma 6 (BCL6) to ATP-competitive inhibitors of cyclin-dependent kinases (CDKs) are developed to re-localize CDK to BCL6-bound loci on chromatin and direct phosphorylation of Pol II. The resulting BCL6-target proapoptotic gene expression translates into killing of diffuse large B-cell lymphoma (DLBCL) cells at 72h with EC50s of 0.9 – 10nM and specific ablation of the BCL6-dependent germinal center response in mice. The molecules exhibit 10,000-fold lower cytotoxicity in normal lymphocytes and are well tolerated in mice. Genomic and proteomic evidence corroborate a gain-of-function mechanism where, instead of global enzyme inhibition, a fraction of total kinase activity is borrowed and re-localized to BCL6-bound loci. The strategy demonstrates how kinase inhibitors can be used to context-specifically activate transcription, accessing new therapeutic space.