Second Generation Hsp90 Inhibitors

We are developing so-called second-generation Hsp90 inhibitors by focusing on (i) the unique pharmacokinetic (PK) and pharmacodynamic (PD) relationship of Hsp90 inhibitors, and (ii) achieving specificity against Hsp90 client proteins which in turn affects efficacy on specific tumor types.

(i) PK / PD Relationships 

The unique biology of Hsp90 tends to cause Hsp90 inhibitors to accumulate at higher levels in tumor tissue than in normal tissue. Our second generation compounds accentuate this effect by more specifically accumulating in tumors and have the potential for significantly enhanced, targeted, tumor destruction. Such an approach is not possible with natural product-derived compounds.

(ii) Specificity against Hsp90 Client Proteins

A number of our second generation lead compounds selectively inhibit specific oncogenic proteins that are chaperoned by Hsp90. Using our proprietary technology, assays and SAR library, we have identified selectivity across 3 axes: tumor selectivity, isoform selectivity and client protein selectivity. This approach may result in increased efficacy against specific cancers while limiting adverse effects on normal tissues.

The Role of Proteome Mining Technology in Developing Second Generation Hsp90 Inhibitors

Our Proteome Mining technology is the only known means of assaying for all four Hsp90 isoforms.  We combine our Proteome Mining technology with high-content cellular assays for Hsp90 and associated client proteins. In addition, we have implemented high-throughput assays for the proliferation of multiple human tumor lines. This unique approach allows us to rapidly profile and assess Hsp90 isoform/client protein interactions occurring in multiple disease states.

Our state-of-the-art assays comprise:

• High resolution multiplex assays for all Hsp90 isoforms using proprietary technology          
• High-content client screens and multiplexed client profiling for in vitro and in vivo profiling          
• High resolution and high throughput human tumor cell proliferation assays

Our small molecule screening technology and SAR data sets provide an unique pool of active molecules with defined binding characteristics across (i) Hsp90 isoforms, (ii) client proteins, and (iii) tumor types. Traditional screening methods are unable to produce this type of selectivity. In short, we have a significant competitive advantage over traditional assay methods and natural product-based compound libraries.  

The wealth of data resulting from Proteome Mining allows us to bypass many of the secondary and tertiary selectivity assays required for traditional approaches. The result is:

• Faster and more focused path to the clinic          
• Reduced potential for off-target toxicities          
• Greater potential for more efficacious drugs

Hsp90 Biomarkers

We are exploring the potential for Hsp90-related diagnostic applications. Using our proteome mining technology, we have identified several biological activities which could lead to specific biomarkers of efficacy or adverse effects in specific patient populations.