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Discovery of Tetrahydropyridopyrimidines as Irreversible Covalent Inhibitors of KRAS-G12C with In Vivo Activity

Jay B Fell1, John P Fischer1, Brian R Baer1

  • 1Array BioPharma, Inc., 3200 Walnut Street, Boulder, Colorado 80301, United States.

ACS Medicinal Chemistry Letters
|January 8, 2019
PubMed

Insights

Researchers developed novel tetrahydropyridopyrimidines that irreversibly inhibit the KRAS-G12C mutation in cancer. This breakthrough offers a promising new therapeutic strategy for difficult-to-treat cancers driven by this common mutation.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Molecular Biology

Background:

  • KRAS is a frequently mutated oncogene in human cancers, often linked to poor prognosis and treatment resistance.
  • Targeting mutated KRAS has been a significant challenge in cancer therapy research.
  • Recent advances show potential in directly inhibiting KRAS-G12C mutations using covalent small molecules.

Purpose of the Study:

  • To discover and develop novel irreversible covalent inhibitors targeting the KRAS-G12C mutation.
  • To evaluate the in vivo activity, pharmacokinetics (PK), and pharmacodynamics (PD) of a lead compound.

Main Methods:

  • Discovery of a series of tetrahydropyridopyrimidine compounds.
  • Design of electrophilic small molecules targeting the cysteine at codon 12 of KRAS-G12C.
  • In vivo studies to assess compound efficacy, PK, and PD.

Main Results:

  • Identification of tetrahydropyridopyrimidines as potent irreversible covalent inhibitors of KRAS-G12C.
  • Demonstration of in vivo activity for the identified inhibitors.
  • Detailed characterization of the PK/PD and efficacy profile of a specific compound (compound 13).

Conclusions:

  • Tetrahydropyridopyrimidines represent a viable class of irreversible covalent inhibitors for KRAS-G12C.
  • The developed compounds show promising in vivo efficacy, offering a new therapeutic avenue.
  • Compound 13 exhibits favorable PK/PD and efficacy, warranting further investigation for cancer treatment.

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