Relocalizing transcriptional kinases to activate apoptosis

Science. 2024 Oct 4;386(6717):eadl5361. doi: 10.1126/science.adl5361. Epub 2024 Oct 4.

Abstract

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.

MeSH terms

  • Animals
  • Apoptosis* / drug effects
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 9* / metabolism
  • DNA / metabolism
  • Humans
  • Lymphoma, Large B-Cell, Diffuse / genetics
  • Lymphoma, Large B-Cell, Diffuse / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Phosphorylation
  • Protein Kinase Inhibitors* / pharmacology
  • Protein Kinase Inhibitors* / therapeutic use
  • Proto-Oncogene Proteins c-bcl-6* / genetics
  • Proto-Oncogene Proteins c-bcl-6* / metabolism
  • RNA Polymerase II* / metabolism
  • Transcription, Genetic

Substances

  • BCL6 protein, human
  • CDK9 protein, human
  • Cyclin-Dependent Kinase 9
  • DNA
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-bcl-6
  • RNA Polymerase II