Killing Two Kinases with One Drug
Cancer cells are characterized by a complex network of interrelated and compensatory signaling driving multiple kinases that reduce their sensitivity to targeted therapy. Strategies that inhibit two or more kinases are needed to block the growth of refractory tumor cells. Researchers at McGill University (Canada), led by Dr. Suman Rao at the Cancer Drug Research Laboratory in the Division of Medical Oncology at McGill University Health Center, created a novel strategy to promote sustained inhibition of two oncogenic kinases.
Clinical attrition rates for multi-targeted agents are significantly lower than those of single-targeted agents, however rational design of multi-targeted drugs is very challenging. Most efforts to inhibit multiple kinases has relied on single chemical scaffolds with overlapping specificity, sometimes called “dirty drugs.” The McGill group used a more rational approach by linking two different, highly selective drugs to produce a single “combi-molecule.” Such combi-molecules can exert their actions as a single molecule or as pro-drugs that cleaved in the cell to produce the two separate inhibitors.
In their recent study in PLOS One, Dr. Rao and colleagues created a combi-molecule for tandem blockage of two tyrosine kinases using highly selective inhibitors for the epidermal growth factor receptor (EGFR) and c-Src, which have synergistic effects on tumor growth and progression. Optimization of the linker group led resulted in discovery of AL776, which showed potent inhibition of both targets in in vitro kinase assays (IC50 EGFR = 0.12 µM and IC50 c-Src = 3 nM). They next demonstrated that the combi-molecule potently inhibited growth and invasion and induced apoptosis in cancer cells. Lastly, they demonstrated that AL776 blocked auto-phosphorylation of both kinases and a downstream target in a mouse tumor model and strongly inhibited tumor growth. The combi-molecule was incompletely hydrolyzed to the two separate inhibitors in cells and in vivo and most likely exerts its effects as a combination of the three species.
This study provides proof of concept for the rational combi-molecule approach for multi-targeted therapies, which has great potential for extension to other targets given the number and diversity of existing kinase inhibitors
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