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Quantifying KRAS G12C Covalent Drug Inhibitor Activity in Mouse Tumors Using Mass Spectrometry.

John C Tran, Thomas Hunsaker, Christina Bell1

  • 1CellCarta, Montreal, Quebec H2X 3Y7, Canada.

Analytical Chemistry
|March 6, 2023
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Summary
This summary is machine-generated.

Developing automated mass spectrometry methods for KRAS G12C inhibitors is crucial for drug discovery. This study presents a streamlined sample preparation technique for measuring drug activity in tumors, improving efficiency for pharmacodynamic studies.

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Area of Science:

  • Biochemistry
  • Pharmacology
  • Analytical Chemistry

Background:

  • Covalent KRAS G12C inhibitors offer therapeutic opportunities but require robust methods for in vivo activity assessment.
  • Current sample preparation for tumor proteins is labor-intensive, limiting throughput for pharmacodynamic (PD) studies.
  • Developing efficient assays is essential for drug discovery and development of targeted therapies.

Purpose of the Study:

  • To describe an automated, integrated sample preparation method for measuring KRAS G12C inhibitor alkylation in complex tumor samples.
  • To enable high-throughput quantitation of drug activity using mass spectrometry.
  • To correlate target occupancy with pharmacodynamic effects in preclinical models.

Main Methods:

  • Automated high-throughput detergent removal and preconcentration of proteins from tumor samples.
  • Quantitation of KRAS G12C drug inhibitor alkylation using mass spectrometry.
  • Assay validation demonstrating low intra-assay (4% CV) and inter-assay (6% CV) variability.

Main Results:

  • The developed method accurately measures KRAS G12C alkylation in mouse tumor samples.
  • The assay exhibits high reproducibility across multiple studies.
  • Demonstrated dose-dependent target inhibition and MAPK pathway inhibition by the KRAS G12C inhibitor GDC-6036.
  • Correlated target engagement with antitumor potency in a pancreatic xenograft model.

Conclusions:

  • An automated sample preparation method significantly enhances the efficiency of measuring covalent KRAS G12C inhibitor activity in tumors.
  • The validated mass spectrometry assay provides a robust tool for PD studies in drug discovery.
  • GDC-6036 exhibits promising dose-dependent efficacy and target inhibition, supporting its potential as an antitumor therapeutic.