Medicinal chemistry strategies to discover P-glycoprotein inhibitors: An update

Area of Science:

• Oncology
• Pharmacology
• Medicinal Chemistry

Background:

• Multidrug resistance (MDR) in cancer, driven by P-glycoprotein (P-gp) efflux, is a major cause of chemotherapy failure.
• Previous generations of P-gp inhibitors showed limited clinical success due to toxicity and efficacy issues.

Purpose of the Study:

• To comprehensively review synthetic and natural compounds with P-gp inhibitory activity.
• To highlight recent advancements in developing potent, selective, and low-toxicity P-gp inhibitors for MDR cancer.
• To focus on structural features, design strategies, and structure-activity relationships (SAR) of these inhibitors.

Main Methods:

• Literature review of synthetic and natural products targeting P-gp.
• Analysis of P-gp inhibitory efficacy and chemosensitizing potential in MDR cancer cells.
• Examination of structural features, design strategies, and SAR of identified compounds.

Main Results:

• Numerous potent, selective, and low-toxicity P-gp inhibitors have been reported recently.
• These compounds demonstrate promising chemosensitizing efficacy in MDR cancer models.
• Detailed SAR analysis provides insights into inhibitor design.

Conclusions:

• Inhibiting P-gp is a promising strategy to overcome MDR in cancer chemotherapy.
• Recent advancements offer new therapeutic avenues for MDR cancers.
• Understanding SAR is crucial for developing effective P-gp inhibitors.