Hsp90 – The target

Heat shock protein 90 (Hsp90) is an important molecular chaperone protein that regulates the folding and degradation of key signaling molecules (client proteins). In disease settings, Hsp90 is concentrated and retained to help stabilize mutated proteins in an effort to retain their functionality. Thus, mutated proteins, such as oncoproteins (proteins that promote the development of cancer cells), are much more sensitive to Hsp90 inhibition than are normal proteins. Hsp90 plays a similar role in a number of other diseases. For example, neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, which are driven by mutated proteins require Hsp90 in order to progress. Fungal infections and viruses require foreign pathogenic proteins to be expressed which also require Hsp90.  Finally, Hsp90 plays a role in the aberrant expression of cytokines and other proteins involved in innate immunity which drive chronic inflammation. In summary, Hsp90 inhibitors are likely to play important roles in multiple indication areas.

Hsp90 Biology

Hsp90 functions as part of a large multi-protein complex consisting of five chaperones and co-chaperones (Hsp90, Hop, p23, Hsp70 and Hsp40). Hsp90 itself, consists of 4 isoforms or family members that affect dozens of client proteins and pathways. These isoforms are:

• Hsp90 alpha and Hsp90 beta cytosolic chaperones           
• Grp94: endoplasmic reticulum (ER) family member              
• TRAP1: mitochondrial family member

In general, Hsp90 inhibitors have higher retention levels in tumors than in normal tissue. At Serenex, we have developed a number of Hsp90 inhibitors that are selectively retained in tumors but not in plasma or normal tissue.  The chart below shows drug concentrations of SNX-2112 in multiple tissues 24 hours and 48 hours after dosing.