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Updated: Mar 3, 2026

Generation of High-Throughput Three-Dimensional Tumor Spheroids for Drug Screening
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Discovery and Characterization of Divarasib (GDC-6036), a Potent Covalent Inhibitor of KRAS G12C

Nicholas F Endres1, Steven Do1, Rana Mroue1

  • 1Genentech, Inc., South San Francisco, California 94080, United States.

Journal of Medicinal Chemistry
|March 2, 2026
PubMed

Insights

Divarasib (GDC-6036) is a potent, selective KRAS G12C inhibitor for nonsmall cell lung cancer. It shows strong anti-tumor effects and rapid kinetics, offering a promising new treatment option.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Molecular Biology

Background:

  • KRAS G12C mutations are key drivers in nonsmall cell lung cancer (NSCLC).
  • Targeting KRAS G12C offers a therapeutic strategy for NSCLC treatment.

Purpose of the Study:

  • To describe the discovery and optimization of divarasib (GDC-6036), a novel KRAS G12C inhibitor.
  • To evaluate the potency, selectivity, and anti-tumor activity of divarasib.

Main Methods:

  • Drug discovery and optimization process for divarasib.
  • In vitro biochemical and cellular assays to assess inhibitor potency and kinetics.
  • In vivo studies evaluating tumor growth inhibition in KRAS G12C-positive models.

Main Results:

  • Divarasib is an orally available, potent, and selective covalent KRAS G12C inhibitor.
  • Divarasib exhibits a significant noncovalent binding component contributing to its potency and rapid kinetics.
  • In vitro studies show divarasib possesses greater potency and alkylation kinetics than other KRAS G12C inhibitors.
  • Divarasib demonstrated robust inhibition of tumor growth in KRAS G12C-positive cell lines.

Conclusions:

  • Divarasib represents a promising therapeutic candidate for KRAS G12C-mutated NSCLC.
  • The unique binding properties of divarasib contribute to its enhanced efficacy.
  • Further clinical investigation of divarasib is warranted for NSCLC treatment.

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