| DESCRIPTION |
During the development of drug candidates, the issue of toxicity inevitably arises. Such undesired effects are also often seen with drugs currently on the market. Whether mild or severe, discovery and elimination of these undesirable effects would increase the success rates in drug development and create safer, more effective drugs. Since these unwanted side effects often occur through interactions of a drug with proteins other than the desired efficacy target(s), identification of these off-target proteins is the first step toward improvement of the drug or drug candidate. With the ability to screen a given compound against a wide array of proteins in a single assay, our technology is ideally suited for the discovery of these unknown, off-target proteins. In addition, the rapidity and high throughput character of our technology is invaluable for the subsequent optimization of drug candidates in the ensuing search for a safer therapeutic compound. As an example, our technology was employed to rescue a stalled Phase I development candidate called Geldanamycin. Geldanamycin is a cancer therapeutic that inhibits the growth of transformed cells in culture. However, it also exhibited severe toxicity. It was believed that Geldanamycin’s therapeutic target was Heat Shock Protein 90 (HSP90). However, the off-target, responsible for the toxicity, was unknown. Our technology was used to identify the protein targets for Geldanamycin. In addition to confirming that the efficacy target was indeed HSP90, a second target, ADE2, was found. ADE2 is involved in purine biosynthesis and it was determined that the inhibition of ADE2 was responsible for Geldanamycin’s toxicity. A focused library of sixty-two Geldanamycin-related compounds was screened to identify candidates that interacted only with HSP90 and not the putative toxicity target. Analogs that were selective for HSP90 retained anti-tumor activity, but displayed significantly reduced general toxicity. Based on these findings, new compounds were selected for development and this program was later successfully outlicensed and is now in Phase II development. |
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