Pharmacokinetic Studies of a Novel c-Met Targeting PROTAC Drug Candidate Using UPLC-MS/MS Quantification Methods

Area of Science:

• Oncology
• Pharmacology
• Biochemistry

Background:

• Gastric cancer remains a significant global health challenge with limited targeted therapies.
• Cellular mesenchymal-epithelial transforming factor (c-Met) kinase is implicated in various cancers, including gastric cancer.
• Proteolysis Targeting Chimeras (PROTACs) represent a novel therapeutic modality for targeted protein degradation.

Purpose of the Study:

• To develop and validate a sensitive analytical method for quantifying the PROTAC drug candidate TPD354 in biological matrices.
• To evaluate the pharmacokinetic properties of TPD354, including its stability and protein binding.
• To assess the therapeutic potential of TPD354 in preclinical gastric cancer models.

Main Methods:

• Ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) was employed for drug quantification.
• The analytical method was rigorously validated for specificity, linearity, precision, accuracy, recovery, and matrix effects.
• Pharmacokinetic studies were conducted in rat models, including assessments of liver microsome stability and plasma protein binding.

Main Results:

• A robust and sensitive UPLC-MS/MS method was established for TPD354 quantification, with a linear range of 6.995-6995.000 ng/mL.
• TPD354 demonstrated metabolic stability in liver microsomes and high plasma protein binding across different species.
• Pharmacokinetic studies in rats revealed a half-life of approximately 16 hours, indicating favorable drug disposition.

Conclusions:

• TPD354 is a promising PROTAC drug candidate targeting c-Met kinase degradation.
• The validated analytical method provides a reliable tool for assessing TPD354 pharmacokinetics.
• TPD354 exhibits favorable preclinical pharmacokinetic and metabolic profiles, supporting its potential for gastric cancer treatment.