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Related Concept Videos

The Ras Gene02:38

The Ras Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a superfamily...
Small GTPases - Ras and Rho01:24

Small GTPases - Ras and Rho

Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
Structure-Activity Relationships and Drug Design01:28

Structure-Activity Relationships and Drug Design

Drug design is a dynamic field that involves discovering and developing new medications based on specific biological targets. This process heavily relies on structure-activity relationships (SAR) and quantitative structure-activity relationships (QSAR) to guide the design and optimization of efficient drugs.
SAR studies the intricate relationship between a drug's chemical structure and biological activity. It focuses on understanding how modifications to a drug's structure can influence its...
GTPases and their Regulation02:14

GTPases and their Regulation

Guanine nucleotide-binding proteins (G-proteins), also known as GTPases, are a superfamily of proteins that regulate many cellular processes, such as cell signaling, vesicular transport, and the regulation of cell shape and motility. Mutation or dysfunction of these proteins can lead to disease. There are around 40,000 known G-proteins that can broadly be classified into two groups ‒  small G-proteins consisting of a single domain and large multi-domain G-proteins.
Large G-proteins, also known...
GPCR Desensitization01:12

GPCR Desensitization

G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
G Protein-coupled Receptors01:15

G Protein-coupled Receptors

G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...

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Related Experiment Video

Updated: Jul 15, 2026

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

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.

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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.