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Combining Fundamental Kinetics and Standard Alkylation Assays to Prioritize Lead-Like KRAS G12C Inhibitors.

Alexandra Frommlet¹, Lan K Nguyen¹, Matt Saabye²

¹Department of Biochemical and Cellular Pharmacology, Genentech, Inc., South San Francisco, California 94080, United States.

|January 6, 2025

Summary

This study introduces a kinetic analysis method for KRAS G12C inhibitors, revealing crucial rate constants for better compound selection. This approach enhances biophysical characterization beyond simple alkylation rates.

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Area of Science:

Biochemistry and Biophysics
Medicinal Chemistry
Drug Discovery

Background:

KRAS G12C is a key oncogenic driver, and its inhibitors are crucial in cancer therapy.
Standard assays often approximate inhibitor kinetics with a single alkylation rate, masking mechanistic details.
Optimal compound prioritization requires a deeper understanding of inhibitor-target interactions.

Purpose of the Study:

To demonstrate the integration of fundamental kinetic rate constants into compound prioritization.
To characterize irreversible covalent KRAS G12C inhibitors using detailed kinetic analysis.
To develop and apply label-free surface plasmon resonance (SPR) methods for measuring transient binding kinetics.

Main Methods:

Characterization of three irreversible covalent KRAS G12C inhibitors.
Estimation of three fundamental kinetic rate constants (k_on, k_off, k_inact) for covalent inhibitors.
Development of label-free SPR methodology for measuring transient binding and kinetic parameters.
Measurement of binding enthalpy using Eyring transition state analysis.

Main Results:

The study successfully estimated the three fundamental kinetic rate constants for KRAS G12C inhibitors.
This detailed kinetic data provides a more complete biophysical characterization compared to a single overall alkylation rate.
The developed SPR methodology enables accurate measurement of transient binding kinetics using standard equipment.
Binding enthalpy measurements offer additional insights for compound prioritization.

Conclusions:

Approximating inhibitor kinetics with a single rate constant sacrifices mechanistic information and increases prioritization risk.
Estimating fundamental kinetic rate constants and binding enthalpy enables more reliable prioritization of lead-like compounds.
This kinetic analysis approach, combined with orthogonal assays, optimizes lead optimization in drug discovery.