Special Chemical Biology Seminar

Protein kinases are disease drivers whose therapeutic targeting traditionally centers on inhibition of enzymatic activity. We leverage chemically induced proximity to convert kinase inhibitors into context-specific activators of therapeutic genes. Bivalent molecules that link ligands of the transcription factor BCL6 to ATP-competitive inhibitors of cyclin-dependent kinases (CDKs) re-localize CDKs to BCL6-bound loci on chromatin and direct phosphorylation of RNA Pol II. The resulting expression of pro-apoptotic BCL6-target genes translates into potent killing of diffuse large B-cell lymphoma (DLBCL) cells and specific ablation of the BCL6-regulated germinal center response in mice. Genomic and proteomic evidence corroborates a gain-of-function mechanism where, instead of global enzyme inhibition or degradation, a small fraction of total kinase activity is borrowed and re-localized. Our findings suggest that the wide range of ATP-competitive inhibitors may be used to borrow, rather than inhibit, kinase activity for therapeutic purposes.