Identification and stabilization of a highly selective gastrin-releasing peptide receptor agonist

Area of Science:

• Oncology
• Pharmacology
• Medicinal Chemistry

Background:

• The gastrin-releasing peptide receptor (GRPR) is a key target in cancer therapy.
• Peptide-drug conjugates targeting GRPR show promise for selective cancer treatment.
• GRPR agonists offer potential for higher tumor uptake via internalization compared to antagonists.

Purpose of the Study:

• To develop novel, small molecule GRPR-selective agonists with improved metabolic stability.
• To identify potent and selective GRPR agonists for targeted cancer therapy applications.

Main Methods:

• Design and synthesis of novel bombesin analogs.
• Evaluation of receptor binding affinity and selectivity for GRPR over other bombesin receptors.
• Assessment of metabolic stability in human blood plasma.

Main Results:

• A novel bombesin analog, [d-Phe⁶ , β-Ala¹¹ , NMe-Ala¹³ , Nle¹⁴ ]Bn(6-14), was developed.
• This analog exhibits high affinity (0.3nM) and selectivity (>4000-fold) for GRPR.
• The analog demonstrated over 75% stability in human blood plasma after 24 hours.

Conclusions:

• The developed GRPR-selective agonist is metabolically stable and highly potent.
• This analog represents a promising drug shuttle for intracellular payload delivery in targeted tumor therapy.