Analyzing Mechanism of Action
Through a former alliance with Exelixis Pharmaceuticals, scientists at Bristol-Myers Squibb (www.bms.com) acquired compounds with beneficial therapeutic effects, but no known target.
The goal was to determine if these compounds would generate phenotypes in model systemsa process called "reverse chemical genetics." If they did, says Petra Ross-MacDonald, Ph.D., senior research investigator, applied genomics, the group used both forward and reverse genetics to modify the phenotype.
Focusing on which genetic changes modified a compound's effect provided clues as to what the compounds were targeting. The company reported two small molecule successes using this approach: a second target for some oncology compounds that could itself be an oncology drug target and a compound that hit signaling through GPCR, but at a novel point.
Although reverse chemical genetics already exists (testing large compound libraries) and has generated data on the effects of compounds in cellular assays, Dr. Ross-MacDonald says that for this to be useful in drug discovery, "we need to know their molecular targets, the proteins they bind."
Also, functional genomics efforts are generating data on the role of particular proteins in cellular assaysand for this to be useful, "we need to know the effects of hitting those proteins with compounds."
"There is a feeling that running the two types of assays in parallel would be a start," adds Dr. Ross-McDonald. Although there is currently no high throughput technology to connect the two types of information, the company says it is looking at areas where it could be advantageous to run compounds and genes in the same assays.