Discovery of Fulzerasib (GFH925) for the Treatment of KRAS G12C-Mutated Solid Tumors

Area of Science:

• Oncology
• Medicinal Chemistry
• Pharmacology

Background:

• RAS mutations, particularly KRAS, are common in human cancers, representing a significant therapeutic challenge.
• KRAS G12C is a specific mutation that has become a druggable target through covalent inhibitors.
• Targeting KRAS G12C offers a promising strategy for specific cancer treatment.

Purpose of the Study:

• To identify and characterize a novel covalent inhibitor targeting the KRAS G12C mutation.
• To evaluate the preclinical efficacy and pharmacokinetic properties of the identified compound, fulzerasib (GFH925).

Main Methods:

• Structure-based drug design was employed to identify fulzerasib.
• In vitro assays were used to assess potency and selectivity.
• Pharmacokinetic studies were conducted across different species.
• In vivo efficacy was evaluated in various cancer xenograft models, including those with intracranial tumors.

Main Results:

• Fulzerasib (GFH925) was identified, featuring a novel naphthyridinone scaffold.
• The compound demonstrated high in vitro potency and selectivity against KRAS G12C.
• Favorable pharmacokinetic profiles were observed in preclinical species.
• Significant in vivo antitumor efficacy was confirmed in multiple xenograft models, including brain tumors.

Conclusions:

• Fulzerasib is a potent and selective covalent inhibitor of KRAS G12C.
• The drug exhibits promising preclinical efficacy and favorable pharmacokinetics.
• Fulzerasib has received accelerated approval in China for KRAS G12C-mutated NSCLC, highlighting its clinical potential.