Targeted and rationally designed irreversible inhibitors are having a positive impact on the treatment of cancer. Ibrutinib is one of the first, rationally designed covalent inhibitors for the treatment of chronic lymphocytic leukemia. It covalently modifies a non-conserved cysteine residue in ATP-binding site of the tyrosine kinase, BTK. Occupancy probes that can assess inhibitor binding to BTK in vivo were essential tools in ibrutinib?s development. However, the use of this approach for other cancer-related targets is limited by cysteine?s scarcity in the proteome. The development of probes that target other nucleophiles is therefore necessary. The Hsp90 family of proteins is a potential target for the treatment of cancer, and there are currently seven Hsp90 inhibitors in clinical trials. Results from these trials have been modest at best. We propose to develop an occupancy probe of the Hsp90 family that covalently modifies a non-catalytic, surface-exposed lysine residue adjacent to the ATP binding site. We will use a structure-guided approach to make covalent inhibitors of the Hsp90 family that use an aryl sulfonyl fluoride as the electrophile. With these probes, we will dissect how inhibition of Hsp90 correlates to client degradation, Hsp70 induction, and cell death. Furthermore, we will explore the advantages of using a covalent inhibitor to treat cancer cells, and will specifically test whether complete, yet transient inhibition of Hsp90 is sufficient to kill cancer cells. Successful development of these probes will represent a significant advance for the scope of covalent probes. Furthermore, these will be the first ATP-binding site directed covalent inhibitors of the Hsp90 family.
There are an estimated 1.5 million new cases of cancer annually, and there remains a need to develop new treatments for cancer. This project takes a novel approach to the design of inhibitors of Hsp90, a potential target for cancer therapy. These inhibitors, and related chemical tools, will contribute to the development of drugs targeting Hsp90 and I will use these inhibitors to better understand how Hsp90 contributes to cancer cell survival.
