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Updated: Sep 25, 2025

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
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Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer

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Discovery of AZD4625, a Covalent Allosteric Inhibitor of the Mutant GTPase KRASG12C

Jason G Kettle1, Sharan K Bagal1, Sue Bickerton1

  • 1Oncology R&D, AstraZeneca, Cambridge CB4 0WG, U.K.

Journal of Medicinal Chemistry
|April 26, 2022
PubMed

Insights

Researchers developed AZD4625, a new drug targeting KRAS G12C-positive tumors. This structure-based drug design offers a potent and selective treatment for difficult-to-treat cancers.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Structural Biology

Background:

  • KRAS is a key oncology drug target, notoriously difficult to inhibit.
  • Specific mutations, like KRAS G12C, present druggable vulnerabilities.

Purpose of the Study:

  • To report the structure-based drug design and identification of AZD4625 (compound 21).
  • To present AZD4625 as a clinical development candidate for KRAS G12C-positive tumors.

Main Methods:

  • Employed structure-based drug design.
  • Utilized a quinazoline tethering strategy for conformational locking.
  • Focused optimization on reducing extrahepatic clearance.
  • Applied crystallographic analysis to understand structure-activity relationships.

Main Results:

  • Identified AZD4625, a potent and selective inhibitor of KRAS G12C.
  • Rationalized structure-activity relationships, including ring size and enantio-preference.
  • Achieved a design with anticipated low clearance and high oral bioavailability in humans.

Conclusions:

  • AZD4625 is a promising clinical candidate for KRAS G12C-driven cancers.
  • The drug design strategy successfully addressed target druggability and pharmacokinetic properties.

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