– Novel drug conjugates that exploit Hsp90 biology to selectively
deliver potent anti-cancer payloads to cancer cells –
– Over 350 HD-Conjugates developed, including HD-Conjugated Alimta®,
Nexavar®, Paraplatin®, Revlimid®, Sutent®, Taxotere®, Velcade®, Zytiga® –
– Broad intellectual property platform; first IND expected in next 18
– Company to host conference call and webcast today at
The need: delivering potent anti-cancer drugs directly to tumors
Current oncology therapeutics generally fall into two categories: cytotoxic agents and molecularly targeted therapies. Cytotoxic agents are often broadly active, but have the disadvantage of high toxicity caused by damage to normal cells, which limits their utility. Drugs that target specific protein drivers of cancer cell growth are generally more tumor selective, yet often lead to tumor resistance via point mutations in their target (e.g. ALK, BRAF, EGFR inhibitors) or activation of alternative signaling pathways (e.g., MEK, ERK, or AKT upregulation).
Targeted delivery strategies, such as Antibody Drug Conjugates (ADCs), offer a solution to these limitations by delivering potent anti-cancer payloads more directly to tumors. HDCs offer many of the advantages of antibody-driven targeted delivery with potentially broader applicability. Because of its unique properties, Hsp90 (heat shock protein 90) may represent one of the most compelling targets for delivering drug payloads to tumors.
HDCs exploit the preferential accumulation of Hsp90-inhibitors in tumors to increase the selective delivery of anti-cancer payloads
Hsp90 is a chaperone protein required by many cancer cells to maintain the stability and function of numerous proteins that drive cancer cell growth, survival, and metastasis. Small molecule inhibitors of Hsp90, including Synta’s drug candidate ganetespib as well as first-generation inhibitors such as 17-AAG and its derivatives, are retained in tumors for as much as 20 times longer than in blood or normal tissue [1, 2]. These properties are believed to be due to overexpression of an active form of Hsp90 in cancer cells as compared to normal tissues, and have been recently applied for tumor imaging [3, 4].
HDCs are drugs consisting of an Hsp90 inhibitor (targeting moiety) joined to an anti-cancer agent (payload) via a cleavable chemical linker optimized for controlled release of payload drug inside cancer cells. Because HDCs are small molecules, they diffuse into the cell passively, avoiding reliance on cell surface antigens or transporters.
Essentially, the active Hsp90 in tumors acts as a magnet to attract the Hsp90-inhibitor moieties in HDCs, bringing the entire HDC molecule preferentially to tumors. This results in higher concentration and longer duration of active payload drug inside cancer cells than occurs with standard administration of unconjugated chemotherapy or other payloads. The enhanced delivery creates the potential for greater cancer cell killing and reduced side effects.