Selective Hsp90Β Inhibitors For The Treatment Of Cancer
Patent Number: Pending
Executive Summary:
General Description:
Hsp90β is one of four Hsp90 isoforms. Hsp90 is a molecular chaperone crucial for the stability and function of many proteins essential for cell survival. 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. 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. 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.
Scientific Progress:
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.
Future Directions:
Strengths:
Selective inhibitor for Hsp90β with low-micromolar anti-proliferative activity in cancer cells
Patent Status:
Legal Status: Application pending
Inventor Bio: Brian Blagg
https://medchem.ku.edu/brian-blagg-research
Executive Summary:
- Invention Type: Therapeutic
- Patent Status: International Application
- Patent Link: https://kuic.ku.edu/available-technologies/selective-hsp90%CE%B2-inhibitors-treatment-cancer
- Research Institute: University of Kansas
- Disease Focus: Cancer
- Basis of Invention: Selective Hsp90β inhibitor
- How it works: Binds the N-terminal ATP-binding pocket of Hsp90β and specifically inhibits the isoform
- Lead Challenge Inventor: Brian Blagg
- Development Stage: In vitro
- Novelty: The invention describes the first N-terminal Hsp90β-selective inhibitor
- Clinical Applications: 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 (cancers, infections, neurodegenerative diseases)
General Description:
Hsp90β is one of four Hsp90 isoforms. Hsp90 is a molecular chaperone crucial for the stability and function of many proteins essential for cell survival. 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. 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. 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.
Scientific Progress:
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.
Future Directions:
- In vivo validation
Strengths:
Selective inhibitor for Hsp90β with low-micromolar anti-proliferative activity in cancer cells
Patent Status:
Legal Status: Application pending
Inventor Bio: Brian Blagg
https://medchem.ku.edu/brian-blagg-research
