Hijacking kinases to kill cancer

The cell cycle—growth, reproduction, and death—is regulated by a complex combination of genes, turned on and off throughout a cell’s life. Enzymes called protein kinases manage this cycle, which is why mutations or overactivity in these regulatory molecules are particularly implicated in the development of cancer and why kinases are important drug targets in oncology research.

The traditional approach is to design kinase-targeting small molecules to inhibit tumor-growth activity, but a team led by Nathanael Gray and Gerald Crabtree at Stanford University has turned this strategy on its head. Rather than try to inhibit cyclin-dependent kinases (CDKs), which uncontrollably activate genes to sustain cell growth in lymphoma, the researchers hijacked the enzymes to become cancer-specific activators of the cell death pathway (Science 2024, DOI: 10.1126/science.adl5361).

Malignant cells down-regulate cell death by overexpressing a transcription factor called BCL6. “Our idea was to borrow a little bit of the activity of the kinase and drag it over to where BCL6 is normally bound on DNA to turn on the entire cell death program that BCL6 is controlling,” first author Sai Gourisankar explains.

The team designed bifunctional molecules that anchor to the BCL6 transcription factor site and reversibly bind CDK enzymes at the other end of the tether. By localizing CDK around the BCL6, the gene-activating effect of the kinase enzymes is directed toward apoptotic genes usually kept silent by the BCL6 transcription factor.

“It’s an interesting and unconventional way to generate a synthetic lethality for this type of cancer,” says Elena De Vita, a chemical biologist at Queen Mary University of London. “The most exciting feature is that it really only targets cells that overexpress BCL6, so it can be quite selective.”

Early in vivo studies revealed low toxicity and high efficacy compared with traditional kinase inhibition strategies—something the team believes is an innate result of its activation mechanism. “For a lot of cancer therapeutics you need 90%, maybe 100% loss of function of a protein to elicit a therapeutic effect. But by making it gain-of-function, we need just a small percentage of CDK to activate the BCL6 target and induce a potent cell death phenotype,” says co-first author Basel Karim.

Pulling two biomolecules together with bifunctional molecules—called induced proximity—is the concept behind proteolysis-targeting chimeras (PROTACS) and molecular glues. But using the approach to cause a cancer driver to activate cell death is new. The team tested one of the molecules, CDK-TCIP2, and showed that it functioned in a rodent model. They are now working to optimizing the medicinal chemistry properties for progression towards pre-clinical studies.

“These molecules alone are of course no magic bullet, but we hope that our work opens doors to developing therapies that harness and redirect kinases more broadly,” says Roman Sarott, co-first author. “We’re excited to expand to completely different cancers and also explore the applications in immunological disorders.”