Design, synthesis and evaluation of PD176252 analogues for ameliorating cisplatin-induced nephrotoxicity

Area of Science:

• Pharmacology
• Oncology
• Toxicology

Background:

• Cisplatin is a widely used chemotherapy drug, but its severe nephrotoxicity and other side effects limit its clinical application.
• PD176252, a gastrin-releasing peptide receptor (GRPR) inhibitor, shows anti-cancer properties but suffers from high toxicity and poor solubility.
• There is a critical need for strategies to mitigate cisplatin's toxicity and improve the therapeutic profile of anti-cancer agents like PD176252.

Purpose of the Study:

• To synthesize and evaluate novel analogues of PD176252 for reduced toxicity, particularly in combination with cisplatin.
• To assess the efficacy of these analogues in mitigating cisplatin-induced nephrotoxicity and inflammatory responses.
• To identify specific analogues with improved safety profiles for potential clinical development.

Main Methods:

• Synthesis of 16 structural analogues of PD176252.
• Evaluation of analogue toxicity in normal HK2 kidney cells.
• In vitro assessment of inflammatory response inhibition in cisplatin-treated cells.
• Comparative analysis of analogue 5d and PD176252 efficacy against cisplatin-induced toxicity.

Main Results:

• Synthesized analogues demonstrated reduced cisplatin-induced renal toxicity.
• Analogues 5d and 5m exhibited negligible toxicity to normal HK2 cells, unlike the parent compound PD176252.
• Analogue 5d effectively inhibited the inflammatory response in vitro, outperforming PD176252 in mitigating cisplatin-induced inflammation.

Conclusions:

• Novel PD176252 analogues, particularly 5d, offer a promising approach to reduce cisplatin's severe side effects.
• Analogue 5d presents an improved safety profile with significantly lower toxicity to normal kidney cells.
• These findings support the potential clinical utility of analogue 5d in enhancing the safety and efficacy of cisplatin-based cancer therapy.