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Updated: Jul 15, 2026

Fully Processed Recombinant KRAS4b: Isolating and Characterizing the Farnesylated and Methylated Protein
07:08

Fully Processed Recombinant KRAS4b: Isolating and Characterizing the Farnesylated and Methylated Protein

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Expanding Addressable KRAS Mutations through the Structure- and Property-Based Design of Dual-State (GDP/GTP),

Ryan P Wurz1, Jennifer R Allen1, John G Allen1

  • 1Medicinal Chemistry, Amgen Research, One Amgen Center Drive, Thousand Oaks, California 91320, United States.

Journal of Medicinal Chemistry
|July 14, 2026
PubMed

Insights

A new pan-KRAS inhibitor, AM-2383, targets diverse KRAS mutations including KRAS G12D and KRAS G12V. This reversible inhibitor effectively suppresses tumor growth, offering a promising new avenue for cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Targeting mutant KRAS is a validated cancer treatment strategy.
  • Existing KRAS G12C inhibitors show promise, driving research into other KRAS mutations.
  • Mutations like KRAS G12D and KRAS G12V are prevalent in various solid tumors.

Purpose of the Study:

  • To design and develop novel, reversible inhibitors targeting diverse oncogenic KRAS mutations.
  • To create a pan-KRAS inhibitor effective against both GDP-bound and GTP-bound states.
  • To evaluate the efficacy of the novel inhibitor in preclinical cancer models.

Main Methods:

  • Structure- and property-based drug design.
  • Development of AM-2383, a pan-KRAS inhibitor.
  • Assessment of AM-2383's inhibitory activity against KRAS isoforms (KRAS, HRAS, NRAS).
  • Evaluation of AM-2383's efficacy in KRAS G12D and KRAS G12V tumor xenografts.

Main Results:

  • AM-2383 was designed as a reversible pan-KRAS inhibitor.
  • AM-2383 selectively targets KRAS, sparing HRAS and NRAS.
  • Oral administration of AM-2383 potently suppressed KRAS G12D and KRAS G12V tumor xenograft growth.
  • AM-2383 disrupts downstream KRAS signaling pathways.

Conclusions:

  • AM-2383 demonstrates proof-of-concept for targeting diverse KRAS mutations.
  • Structural insights from KRAS G12C inhibitors can guide the development of new KRAS therapies.
  • AM-2383 shows potential as an efficacious and well-tolerated cancer therapeutic.

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