Alternative Approaches to Overcome the Detriments Associated with pan-Hsp90 Inhibition

The Hsp90 family of molecular chaperones plays essential roles in the proper folding and maturation of a diverse range of client substrates. The Blagg research group utilizes a multifaceted approach of medicinal chemistry, organic chemistry, and biochemistry techniques to develop small molecule therapeutics that target these chaperones of interest. Their goal is to employ innovative strategies to target Hsp90, thereby mitigating the detriments associated with pan-Hsp90 inhibition.

Within this framework, my dissertation research has consisted of the design, synthesis, and evaluation of small molecule Hsp90 inhibitors. These strategies involved the discovery of novel Hsp90 C-terminal inhibitors designed from DNA gyrase B analogs, the optimization of a benzamide-based Grp94-selective scaffold that utilizes an “induced fit” binding model, and the development of Grp94-selective amide analogs of the KUNG65 scaffold.

Data obtained during these studies assisted in the validation of the direction and design of both Hsp90 C-terminal inhibitors, and Grp94-selective small molecules. Inhibitors developed from these studies can be further utilized to study the Hsp90 C-terminal domain, as well as the structure and conformational dynamics of the Grp94 N-terminal ATP binding pocket.