Anti-Infectives

By chaperoning a fungal protein phosphatase involved in cell cycle progression, Hsp90 enables pathogenic fungi such as Candida albicans and Aspergillus fumigatus, to develop resistance against anti-fungal agents. Drug resistance to common agents such as fluconazole is reversed by the addition of an Hsp90 inhibitor.  Further, when combined with an anti-fungal agent, Hsp90 inhibition converts the activity of the anti-fungal from growth inhibition to lethality.  By working with key academic collaborators, we have generated in vitro and in vivo proof-of-concept data for proprietary Hsp90 inhibitors as anti-fungals.  Internally, we are optimizing compounds for this indication.

Hsp90 inhibitors also play important roles as anti-viral agents.  Key viral proteins (such as the RNA dependent RNA polymerases of RNA viruses) require Hsp90 for structural integrity and stability.  By degrading these viral proteins Hsp90 inhibitors effectively act as anti-viral agents. Serenex is working with academic collaborators in this field and has generated in vitro proof of concept.

Neurodegenerative Diseases

It is thought that many neurodegenerative diseases are characterized by misfolded, hyper-phosphorylated and mutated proteins. These pathogenic forms of proteins (such as the tau protein) show an increased dependence on Hsp90 for conformational stability.  As a result, Hsp90 inhibition is receiving a great deal of attention as a means to intervene in these diseases.  There is also an additional mechanistic benefit to Hsp90 inhibitors for this application.  One effect of inhibiting Hsp90 is to induce other molecular chaperones, such as Hsp70 and Hsp27.  Hsp70 and Hsp27 are associated with protein aggregates (e.g. amyloid-beta, Lewy bodies, neurofibrillary tangles) characteristic of Alzheimer, Parkinson's and other diseases. Emerging evidence indicates that these fibrillar aggregates are not pathogenic but rather are an effort by the body to sequester toxic species in an inert complex.  Hsp90 inhibitors have been shown to have desirable effects on neurodegenerative processes both in vitro and in vivo.  We have generated In vitro proof of concept data and have identified compounds with favorable brain pharmacokinetics.  Internally, we are optimizing compounds for these indications.

Anti-Inflammatory Disease

Hsp90 has been shown to play a role in chronic acute inflammation, which drives diseases such as rheumatoid arthritis. Under these cellular stress conditions Hsp90 levels are elevated for protein stability.  As an example, Hsp90 has been shown to play a role in the inflammasome, a multi-protein complex regulating innate immunity and inflammation. Angiogenic signaling proteins, implicated in both oncology and inflammation, are also sensitive Hsp90 clients. We have Hsp90 inhibitors that block production of key inflammatory mediators in vitro and exhibit anti-inflammatory activity in vivo. We are currently optimizing compounds for this indication.