Relocalizing transcriptional kinases to activate apoptosis

• Published in: Science (American Association for the Advancement of Science) 2024-10, Vol.386 (6717), p.eadl5361
• Main Authors: Sarott, Roman C, Gourisankar, Sai, Karim, Basel, Nettles, Sabin, Yang, Haopeng, Dwyer, Brendan G, Simanauskaite, Juste M, Tse, Jason, Abuzaid, Hind, Krokhotin, Andrey, Zhang, Tinghu, Hinshaw, Stephen M, Green, Michael R, Crabtree, Gerald R, Gray, Nathanael S
• Format: Article
• Language: English
• Subjects: Ablation; Animals; Apoptosis; Apoptosis - drug effects; Bcl-6 protein; Binders; Biodegradation; Cancer; Catalytic activity; Cell death; Cell Line, Tumor; Cell membranes; Cell proliferation; Chemical activity; Chemical properties; Cyclin-dependent kinase; Cyclin-Dependent Kinase 9 - metabolism; Cyclin-dependent kinases; Cytotoxicity; Deregulation; DNA - metabolism; DNA-directed RNA polymerase; Drug delivery; Drug development; Elongated structure; Enzyme inhibitors; Epigenetics; Gene expression; Genes; Germinal centers; Humans; Immunization; Inhibitors; Kinases; Ligands; Lymphocytes; Lymphocytes B; Lymphoma; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Large B-Cell, Diffuse - metabolism; Mice; Mice, Inbred C57BL; Mortality; Pharmacology; Phosphorylation; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proteins; Proto-Oncogene Proteins c-bcl-6 - genetics; Proto-Oncogene Proteins c-bcl-6 - metabolism; Quorum sensing; Ribonucleic acid; RNA; RNA polymerase; RNA polymerase II; RNA Polymerase II - metabolism; Therapeutic applications; Therapeutic targets; Transcription factors; Transcription, Genetic; Transcriptomics; Tumor cell lines
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.adl5361

Kinases are critical regulators of cellular function that are commonly implicated in the mechanisms underlying disease. Most drugs that target kinases are molecules that inhibit their catalytic activity, but here we used chemically induced proximity to convert kinase inhibitors into activators of therapeutic genes. We synthesized bivalent molecules that link ligands of the transcription factor B cell lymphoma 6 (BCL6) to inhibitors of cyclin-dependent kinases (CDKs). These molecules relocalized CDK9 to BCL6-bound DNA and directed phosphorylation of RNA polymerase II. The resulting expression of pro-apoptotic, BCL6-target genes caused killing of diffuse large B cell lymphoma cells and specific ablation of the BCL6-regulated germinal center response. Genomics and proteomics corroborated a gain-of-function mechanism in which global kinase activity was not inhibited but rather redirected. Thus, kinase inhibitors can be used to context-specifically activate transcription.