Four-year research project seeks broad insights into the mechanisms of kinase inhibitors

The National Institute of Diabetes and Digestive and Kidney Diseases awarded a more than $2 million grant to study the mechanisms of kinase inhibitors to Navjot Pabla, PhD, associate professor of pharmaceutics and pharmacology at The Ohio State University College of Pharmacy, and Amandeep Bajwa, PhD, associate professor of medicine at the University of Tennessee Health Science Center.

Their study titled, “Off target mechanisms of Kinase Inhibitor toxicities,” will span a four-year period and will seek broad insights into the pharmacological action of kinase inhibitors – medications that decrease the function of the protein kinase enzymes.

Protein kinases are important because they regulate the activity of proteins in the body and orchestrate the transmission of information between the cells, both essential for normal cellular functions. An imbalance of kinase activity is both a cause and consequence of several human diseases, especially cancer.

Because kinase inhibitors are highly successful in decreasing aberrant kinase activation, more than 70 drugs have been approved – mostly for oncological diseases. However, even though these medications can successfully target kinases, recent studies show that the same medications can inhibit other proteins, like ferrochelatase (FECH), which is a key mitochondrial protein.

This off-target inhibition influences drug responses, especially toxicities, but the mechanisms have remained unknown. Drs. Bajwa and Pabla’s research seeks to understand how kinase inhibitors are transported into normal cells, how the subsequent FECH inhibition drives mitochondrial dysfunction and how these pathways are differentially regulated in males versus females.

These studies are expected to provide broad insights into the pharmacological action of kinase inhibitors in normal tissues, including cellular uptake, non-kinase target inhibition, mitochondrial dysfunction and transcriptional mechanisms underlying gender differences in toxicities.

“This grant will allow us to understand how protein kinase inhibitors influence mitochondrial functions and cause toxicity in tissues such as the kidneys,” Dr. Bajwa said. “These findings could lead to identification of mechanism-based approaches to mitigate debilitating toxicities in cancer patients.”

 “Understanding how protein kinase inhibitors cause toxicities through off-target effects have remained an underexplored area and our proposed studies are expected to provide new insights into the pharmacology of kinase inhibitors,” Dr. Pabla said.