Relocalizing transcriptional kinases to activate apoptosis

Area of Science:

• Molecular Biology
• Biochemistry
• Cancer Research

Background:

• Kinases are key regulators of cell function and are frequently involved in disease pathogenesis.
• Current kinase-targeting drugs primarily function by inhibiting catalytic activity.
• Developing novel therapeutic strategies that leverage kinase activity is crucial for treating diseases like cancer.

Purpose of the Study:

• To explore the use of chemically induced proximity to convert kinase inhibitors into gene activators.
• To investigate the potential of bivalent molecules linking BCL6 ligands and CDK inhibitors for therapeutic gene activation.
• To assess the efficacy of this approach in targeting diffuse large B cell lymphoma (DLBCL) and the germinal center response.

Main Methods:

• Synthesis of bivalent molecules connecting B-cell lymphoma 6 (BCL6) ligands with cyclin-dependent kinase (CDK) inhibitors.
• Utilizing chemically induced proximity to relocalize CDK9 to BCL6-bound DNA.
• Assessing the phosphorylation of RNA polymerase II and subsequent gene expression.
• Employing genomics and proteomics to analyze the mechanism of kinase activity redirection.

Main Results:

• Bivalent molecules successfully relocalized CDK9 and induced RNA polymerase II phosphorylation.
• Expression of pro-apoptotic, BCL6-target genes led to the killing of DLBCL cells.
• Specific ablation of the BCL6-regulated germinal center response was observed.
• Genomics and proteomics confirmed a gain-of-function mechanism involving redirected kinase activity.

Conclusions:

• Kinase inhibitors can be repurposed as activators of therapeutic gene transcription through context-specific targeting.
• Chemically induced proximity offers a novel strategy for modulating kinase activity for therapeutic benefit.
• This approach demonstrates potential for treating BCL6-driven malignancies and other diseases involving kinase dysregulation.