Borrowing Transcriptional Kinases to Activate Apoptosis
Sarott, R. C.; Gourisankar, S. P.; Karim, B. A.; Nettles, S.; Yang, H.; Dwyer, B.; Simanauskaite, J. M.; Tse, J.; Abuzaid, H.; Krokhotin, A.; Zhang, T.; Hinshaw, S. M.; Green, M. R.; Crabtree, G. R.; Gray, N.
Show abstract
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) were developed to re-localize CDK to BCL6-bound loci on chromatin and direct phosphorylation of RNA Pol II. The resulting BCL6-target proapoptotic gene expression translated into killing of diffuse large B-cell lymphoma (DLBCL) cells at 72 h with EC50s of 0.9 - 10 nM and highly specific ablation of the BCL6-regulated germinal center response in mice. The molecules exhibited 10,000-fold lower cytotoxicity in normal lymphocytes and are well tolerated in mice. Genomic and proteomic evidence corroborated 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.
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