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

Yan Gao1, Xinyu Li1, Chao Xin2

  • 1College of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang, China.

Biopharmaceutics & Drug Disposition
|January 14, 2026
PubMed
Summary

TPD354, a novel Proteolysis Targeting Chimera (PROTAC), effectively degrades c-Met kinase. This drug candidate demonstrated significant efficacy in gastric cancer models and exhibits favorable pharmacokinetic properties for further development.

Keywords:
PROTACUPLC‐MS/MSc‐Met degradationpharmacokinetics

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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.