Pharmacological effectors of GRP78 chaperone in cancers

Area of Science:

• Molecular Biology
• Oncology
• Drug Discovery

Background:

• The protein chaperone GRP78 (glucose-regulated protein 78) is crucial for endoplasmic reticulum (ER) function.
• GRP78 overexpression on cancer cell surfaces is linked to chemo-resistance, making it a significant therapeutic target.
• Despite its role, GRP78 remains an under-explored target for novel drug development.

Purpose of the Study:

• To review the structural and functional diversity of GRP78 modulators.
• To explore therapeutic strategies targeting GRP78, including natural products, synthetic molecules, peptides, and antibodies.
• To assess the potential of GRP78 inhibitors as anticancer therapeutics, particularly for overcoming chemo-resistance.

Main Methods:

• Comprehensive literature review of GRP78 modulators and targeting strategies.
• Analysis of over 130 natural products, synthetic molecules, peptides, and monoclonal antibodies.
• Examination of approaches to modulate GRP78 activity, including direct binding, expression regulation, and cellular trafficking interference.

Main Results:

• A wide array of GRP78 modulators have been identified, including direct-binding molecules targeting the ATP site.
• Strategies involving oligonucleotides and cell-delivery peptides conjugated to cytotoxic payloads are presented.
• The review maps out pharmacological effectors of GRP78, highlighting its potential as a drug target.

Conclusions:

• GRP78 repressors show promise as anticancer therapeutics by potentially overcoming chemo-resistance.
• Targeting GRP78 offers diverse therapeutic avenues, including direct inhibition and modulation of its expression or trafficking.
• The potential of GRP78-targeting drugs extends to other therapeutic modalities beyond cancer treatment.