Synergistic Drug Combinations
The traditional drug discovery paradigm of “one-drug, one-target” may soon be replaced by a new approach that targets synergy in biological systems, according to scientists at CombinatoRx (www.combinatorx.com). “Researchers are increasingly recognizing the complexity of biological networks, and the need for coordinated action at multiple molecular targets,” says Glenn Short, Ph.D., senior scientist, technology and platform development. “In order to boost both efficacy and specificity of drugs, agents that target multiple pathways are needed.”
Grant Zimmerman, Ph.D., director of discovery sciences and technology, agrees. “Identifying multitarget therapeutics requires a different discovery approach. Our company has developed a combination high-throughput screening technology, cHTS™, that allows rapid and effective surveys of millions of combinations of drugs to identify synergistic combinations of compounds acting at multiple points within cellular networks.
“This is particularly important and unique to CombinatoRx because these combinations can reveal unexpected interactions between signaling pathways or genes that traditional discovery methods would miss. Another advantage is that synergistic combination pharmaceuticals often can be used at lower doses than needed for single use, thus reducing potential side effects.
“This cHTS technology rapidly screens thousands of compounds using disease-relevant phenotypic assays to detect synergistic multitarget mechanisms. To make this possible, we have developed custom analytical solutions, specific numerical models, databases, and novel hardware and software,” notes Dr. Zimmerman.
Initially, the company looked at combinations of many different known drugs. According to Curtis Keith, Ph.D., senior vp of research, “This first-tier approach was taken because known drugs have recognized pharmacology, toxicity, and safety profiles as well as proven manufacturing processes. Now, we are beginning to expand our approaches to discover combinations of different types of agents such as chemical probes, siRNAs, and antibodies.”