Selective Hsp90β Inhibitors for the Treatment of Cancer
This invention describes the first selective inhibitor of heat shock protein 90 kDa beta (Hsp90β). The invented inhibitor selectively binds to the N-terminus of Hsp90β and may be developed for the treatment of cancers. The inhibitor was developed based on the sequence alignment of the N-terminal ATP-binding domains of Hsp90α and Hsp90β complexed with a non-selective Hsp90 inhibitor, which revealed Hsp90β-specific residues that were key to exploit the selectivity of the new inhibitor.
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 >95% 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.
The invented, highly selective Hsp90β inhibitors can be developed for the treatment of a variety of diseases that result from increased Hsp90 expression while avoiding the off-target effects of pan inhibition.
The co-crystal structures of a non-selective Hsp90 inhibitor, bound to either Hsp90α or Hsp90β enabled the design of the first Hsp90β-selective inhibitor. Sequence alignment of the N-terminal ATP-binding domains of both isoforms revealed an important characteristic that differentiates Hsp90β from Hsp90α. By exploiting this difference, the inventors developed an inhibitor of the Hsp90β isoform that exhibits more than 50-fold selectivity over Hsp90α.
The invention describes the first N-terminal Hsp90β-selective inhibitor. The inhibitor exhibited more than 50-fold selectivity over Hsp90α and low-micromolar anti-proliferative activity against cancer cells (non-small cell lung cancer, bladder cancer, and colon cancer), while leading to the degradation of Hsp90β-client proteins CXCR4 and CDK-4/6.
Existing Hsp90 inhibitors are non-selective for Hsp90β; suitably, the inhibitor presented in this invention exhibits selectivity for Hsp90β with low-micromolar anti-proliferative activity in cancer cells (over normal cells). The inhibitor also induces degradation of select Hsp90β-dependent proteins without concomitant induction of Hsp90 expression, an effect observed from pan inhibition of non-selective inhibitors.
Drug development for the treatment of multiple diseases, including cancers, infections, and neurodegenerative diseases.