My research in the Chiosis laboratory is focused on the study of stress-specific heat shock protein complexes with a purpose of developing effective therapeutics. The complexes are characteristics of cancer and, potentially, other diseases where they promote the pathogenic phenotype of cells. The chaperones Hsp90 and Hsc70 are major components of these complexes. This suggests that targeting of Hsp90 and Hsp/c70 in a specific complex state would lead to a better therapeutic outcome. As a part of this project, together with my colleagues, we have characterized these complexes and developed methods to identify tumors that express such heat shock protein complexes and therefore could respond to HSP-targeted compounds developed in the laboratory. Currently, we are translating these methods to patient samples to provide selection of the patients that can benefit the most from the heat shock protein targeting therapy.
Another way to interrogate Hsp90 machinery in cancer is through targeting Hsp70. Towards this goal we have discovered an inhibitor of a previously unknown Hsp70 site, YK5. I have shown that in cancer cells, this compound is a potent and selective binder of the cytosolic Hsp70s. It interferes with the formation of active oncogenic Hsp70/Hsp90/client protein complexes and is associated with inhibition of cell growth and induction of apoptosis. YK5 is a part of the first rationally designed Hsp70 inhibitor class. The scaffold represents a viable starting point for the development of druglike Hsp70 inhibitors as novel anticancer therapeutics. Optimization of this class of compounds by the chemists in the laboratory led to the development of high potency agents that are on the way to clinical translation. As a part of this project, we have designed and developed YK5-based affinity purification chemical toolset for potential use in the investigation of the endogenous Hsp70-interacting proteome in cancer. We demonstrated that these tools purify Hsp70 in complex with onco-client proteins and effectively isolate Hsp70 complexes for identification through biochemical techniques. Using the affinity probes will provide information on the cell-specific endogenous effects and mechanisms associated with Hsp70 in cancer and other diseases.