KCS

Over the past two decades, molecularly targeted therapies have been discovered to more accurately identify and attack cancer cells, while causing little damage to normal cells. These “one disease-one target approach” are prevalent paradigm in pharmaceutical industry and several targeted drugs such as Gleevec (Novartis), Herceptin (Genentech) and Iressain (AstraZeneca) have been approved by FDA for the treatment of cancers. Despite their superiority in their therapeutic efficacy and selectivity, recent evidence has shown that most single-target drugs encounter the emergence of drug resistance in long-term use. The tumor cells outsmart single-target drugs to escape from their destiny by mutating target protein or finding new pathway to achieve tumor growth that does not depend on target protein. In this regard, heat shock protein 90 (Hsp90) has emerged as an attractive therapeutic target in cancer research. Hsp90 is an ATP dependent molecular chaperone that is required for the stability and maturation of numerous ‘client’ proteins. These client proteins include EGFR, Her2, Met, Cdk4, Akt, Hif-1, all of which are known to be involved in various signaling pathways for the survival, proliferation, invasion and metastasis of cancer cell. Accordingly, the inhibition of Hsp90 function promotes ubiquitin-dependent proteasomal degradation of diverse client proteins, which can eventually overcome the drug resistance and lead to cell death. As part of our ongoing efforts to discover small molecules targeting N-terminal ATP-binding pocket of Hsp90, we had performed a structure-based drug design (SBDD) of small molecule inhibitors, synthesized and evaluated their biological activities against Hsp90. Here, we present our effort to develop therapeutic agents against Hsp90.