Selecting the first chemical molecule inhibitor of HSP110 for colorectal cancer therapy

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Heat shock protein 110 (HSP110) is a pro-survival chaperone with a known inactivating mutation linked to excellent prognosis in colorectal cancer.
• Identifying therapeutic targets within HSP110 pathways is crucial for developing novel colorectal cancer treatments.

Purpose of the Study:

• To identify and characterize inhibitors of HSP110 for potential colorectal cancer therapy.
• To investigate the mechanism of action of identified HSP110 inhibitors on cancer cell growth and client protein interactions.

Main Methods:

• Integrated crystallographic studies of human HSP110 with in silico modeling.
• Selection of candidate inhibitors (foldamers 33 and 52) from a chemical library using various biochemical assays (co-immunoprecipitation, AlphaScreening, Interference-Biolayer, Duo-link).
• Assessment of inhibitor effects on HSP110 chaperone activity, STAT3 phosphorylation, colorectal cancer cell proliferation, and tumor growth in animal models.

Main Results:

• Two novel HSP110 inhibitors, foldamers 33 and 52, were identified, binding to the nucleotide-binding domain.
• These foldamers inhibit HSP110's anti-aggregation activity and its association with STAT3, leading to reduced STAT3 phosphorylation and colorectal cancer cell growth.
• Foldamer 33 demonstrated significant tumor growth inhibition in colorectal cancer animal models with no observed toxicity, inducing apoptosis in tumor cells.

Conclusions:

• The study presents the first identified HSP110 inhibitors, foldamers 33 and 52, with therapeutic potential for colorectal cancer.
• These inhibitors offer a promising drug candidate, particularly for colorectal cancer patients with unfavorable prognoses linked to HSP110.
• The findings support targeting HSP110 as a viable strategy in colorectal cancer treatment development.