RESEARCHERS have developed an innovative approach to treat cancers driven by kinase mutations, specifically targeting B cell lymphoma. By designing bivalent molecules known as CDK-transcriptional/epigenetic chemical inducers of proximity (CDK-TCIPs), the team has created a novel strategy to treat cancers like diffuse large B cell lymphoma (DLBCL), which is often fuelled by the overexpression of the BCL6 transcription factor.
Cyclin-dependent kinases (CDKs), which regulate transcription, are crucial for both cancer cell survival and normal cell function. Traditionally, researchers have aimed to inhibit or degrade CDKs to combat cancer, but this approach carries risks due to the essential role of CDKs in healthy cells. The new strategy, however, converts CDKs into targeted activators of cancer-specific genes that promote cell death, avoiding the broader toxicity of traditional inhibitors.
CDK-TCIPs link inhibitors of CDK9, a key subunit of the P-TEFb complex, with BCL6-targeting compounds, focusing the activity of CDKs on the BCL6 gene. This induces the activation of pro-apoptotic genes and selectively kills BCL6-overexpressing lymphoma cells. Remarkably, these molecules were found to be 100 times more potent in killing lymphoma cells than conventional treatments and 200 times less toxic to normal lymphocytes.
This approach, which also works with CDK12 and CDK13 inhibitors, offers a potential new therapeutic avenue for cancers and autoimmune diseases. The team’s findings open the door to a new class of targeted therapies that exploit kinase activity to specifically activate cell death genes, providing a promising strategy for overcoming cancer resistance.
Reference
Sarott R et al. Relocalizing transcriptional kinases to activate apoptosis. Science. 2024;386(6717):eadl5361.
