Hsp90β selective inhibitors for cancer
Highly selective Hsp90β inhibitors can be developed for the treatment of a variety of diseases that result from increased Hsp90 expression.
Hsp90 is a molecular chaperone crucial for the stability and function of many proteins essential for cell survival. The Hsp90 family of proteins consists of four isoforms: Hsp90β, Hsp90α, Grp94, and Trap-1, which together are responsible for the conformational maturation, activation, and/or trafficking of approximately 300 Hsp90-dependent proteins.
Many Hsp90-client proteins, including tyrosine kinases, transcription factors, and cell-cycle regulatory proteins, are crucial to the pathogenesis of many cancers, neurodegenerative diseases, and infections. In neoplastic cells, increased Hsp90 expression stabilizes oncogenic proteins; thus, overexpression of Hsp90 can promote independence of growth factors, tumor-cell survival, proliferation, immortalization, neovascularization, and metastasis. Hsp90 inhibition causes client protein degradation via the ubiquitin–proteasome pathway that may simultaneously downregulate several redundant pathways crucial for cell viability and tumor development. Therefore, Hsp90 is a promising target for the development of anti-cancer chemotherapeutics.
However, most Hsp90 inhibitors exhibit pan inhibition, which may contribute to adverse side effects and limit their clinical translation. As a result, the development of isoform-selective Hsp90 inhibitors is currently being investigated to delineate the role of each Hsp90 isoform and exploit differences that can lead to therapeutics with increased isoform specificity. However, because the N-terminal ATP-binding site of the cytosolic isoforms Hsp90α and Hsp90β is more than 95 percent identical, the development of inhibitors selective for either isoform is a current challenge. This invention describes the development of selective Hsp90β-binding agents from exploiting a two-residue difference between the N-terminal ATP-binding sites of Hsp90α and Hsp90β.
Learn more here.