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Updated: May 30, 2025

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Design, Structure Optimization, and Preclinical Characterization of JAB-21822, a Covalent Inhibitor of KRASG12C

Amin Li1, Sujing Li1, Peng Wang2

  • 1Medicinal Chemistry Department, Jacobio Pharmaceuticals Group Co., Ltd., Beijing 100176, P. R. China.

Journal of Medicinal Chemistry
|January 28, 2025
PubMed

Insights

A new drug, JAB-21822, effectively targets the KRAS G12C mutation common in cancers like lung cancer. This covalent inhibitor shows high potency and favorable pharmacokinetics, advancing to clinical trials.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Pharmacology

Background:

  • KRAS is a key driver oncogene in various human cancers.
  • The KRAS G12C mutation is prevalent in non-small-cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC).
  • Targeting KRAS G12C with covalent inhibitors is a promising therapeutic strategy.

Purpose of the Study:

  • To design and optimize novel covalent KRAS G12C inhibitors using structure-based drug design.
  • To identify a potent and pharmacokinetically optimized inhibitor for clinical development.

Main Methods:

  • Structure-based design and cocrystal-aided optimization of 1,8-naphthyridine-3-carbonitrile compounds.
  • Biopharmaceutical optimization to enhance solubility and metabolic stability.
  • Preclinical evaluation of lead compounds, including JAB-21822.

Main Results:

  • Identification of JAB-21822, a potent covalent KRAS G12C inhibitor.
  • JAB-21822 exhibits high potency and excellent cross-species pharmacokinetic properties.
  • JAB-21822 has successfully completed Phase II clinical trials in NSCLC.

Conclusions:

  • JAB-21822 represents a promising therapeutic candidate for KRAS G12C-mutated cancers.
  • The drug's favorable profile supports its advancement in clinical development.
  • A new drug application for JAB-21822 was submitted in 2024.

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