Mechanism of Paullones on Kinase Families

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In recent studies, Paullones, a class of benzazepinones, have proven to be potent inhibitors of primarily, two protein kinase families: Cyclin Dependent Kinases as well as the Glycogen Synthase Kinase family. Cyclin dependent Kinase, also known as the CDK family is critical for the regulation of specific cell cycle phases as well as subcellular organelle alignment1.  The deregulation of CDKs can lead to tumor formation. Therefore, targeting defunct CDKs, is critical for cancer prevention and treatment. Kenpaullone, particularly was proven to be a competitive inhibitor via an ATP-binding site of CDK. According to the research efforts of Zaharevitz and his team, Kenpaullone has a distinct chemical structure that binds to the ATP binding site of CDK and therefore inhibits its activity and ultimately prevents tumor formation.

Glycogen synthase kinase, or GSK pathway, plays a role in Alzheimers disease.  Patients with Alzheimers, have a problem with their tau proteins. Tau proteins are found in neurons and they basically facilitate stabilization of microtubules.  GSK-3 is one of the enzymes responsible for the hyperphosphorylation of the tau protein, a feature of which is observed in the brains of patients with Alzheimers . Therefore hyperphosphorylation destabilizes neuronal microtubules2.  The other enzyme involved in hyperphosphorylation of the tau proteinis neuronal CDK5/p25. The normal function of CDK5, involves apoptosis of primary neurons. However, if the enzyme is heavily phosporylated, it can lead to neurodegenerative diseases such as Alzheimers. In the study conducted by Leost, his team proved thatalsterpaullone is a potent and selective inhibitor of both GSK-3α/β as well as CDK5/p25. It was demonstrated that alsterpaullone prevented in-vivo phosphorylation of the tau protein at a specific site in GSK-3β.

Paullones have proven to be the small yet potent class of molecules that could play a critical role in the prevention of not only certain cancers but to neurogenerative disorders, such as alzheimers.

References

1.Zaharevitz, D. W., Gussio, R., & Maryse, L. (1999). Discovery and Initial Characterization of the Paullones, a Novel Class of Small-Molecule Inhibitors of Cyclin-dependent Kinases. Cancer Research, (59), 2566-2569.

2.Maryse, L., Schultz, C., & Link, A. (2000). Paullones are potent inhibitors of glycogen synthase kinase-3B and cyclin-dependent kinase 5/p25. Eur. J. Biochem, 267, 5983-5994.