Virtual and experimental high throughput screening identifies a proteasome inhibitor highly selective for inducing apoptosis of cancer cells over normal cells

2202 The fact that many proapoptotic proteins are degraded by the proteasome prompted the development of proteasome inhibitors (PIs) as anticancer drugs. Although the PI Velcade has been approved for the treatment of multiple myeloma, the search for PIs with lower toxicities to normal cells continues. To this end, we have screened about 3000 compounds from the NCI against the chymotrypsin-like activity of the 20S proteasome. One of the confirmed hits PI-301 inhibits the proteasome chymotrypsin activity of cancer but not normal cells (IC50 of 2μM) and accumulates two major substrates of the proteasome, the pro-apoptotic protein Bax and the CDK inhibitor p27kip. Importantly, in 3 sets of cancer cell lines with their normal counterparts from breast, pancreatic and ovarian origin, PI-301 inhibited proliferation and induced apoptosis in the cancer cells but not in the normal counterparts. Therefore, we have identified a novel PI which is highly selective for cancer cells and is non-toxic to normal cells.