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Tissue distribution and retention drives efficacy of rapidly clearing VHL-based PROTACs

Donglu Zhang1, Bin Ma2, Peter S Dragovich2

  • 1Genentech; 1 DNA Way, South San Francisco, CA, 94080, USA. zhang.donglu@gene.com.

Communications Medicine
|May 16, 2024
PubMed
Abstract

Insights

Proteolysis-targeting chimeras (PROTACs) distribute rapidly into tissues, accumulating in organs like the lung and liver. Understanding this tissue distribution is key for optimizing PROTAC therapeutic dosing and efficacy.

Area of Science:

  • Pharmacology
  • Biochemistry
  • Oncology

Background:

  • Proteolysis-targeting chimeras (PROTACs) are emerging therapeutics with potential clinical applications.
  • However, their poor pharmacokinetic profiles and unknown tissue distribution kinetics hinder development.

Purpose of the Study:

  • To investigate the tissue distribution kinetics of a VHL-PROTAC (14C-A947) in rats and mice.
  • To elucidate in vivo clearance pathways and evaluate cell uptake/retention mechanisms.

Main Methods:

  • Quantitative whole-body autoradiography (QWBA) and tissue excision in rats and mice following IV dosing.
  • Bile duct-cannulated (BDC) rats were used to determine clearance pathways.
  • In vitro studies assessed cell uptake and retention properties.

Main Results:

  • 14C-A947 rapidly distributed into rat tissues, accumulating in the lung and liver despite fast systemic clearance.
  • Tumor growth inhibition was observed in a lung cancer model, correlating with tissue uptake/retention kinetics.
  • Solute carrier (SLC) transporters mediate hepatocyte uptake, and sustained protein degradation occurred due to prolonged cell retention.

Conclusions:

  • Plasma concentrations do not accurately reflect tissue concentrations for VHL-PROTAC efficacy.
  • Understanding PROTAC tissue uptake and retention is crucial for optimizing therapeutic dosing strategies, potentially allowing less frequent administration.

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