Discovery of AZD4747, a Potent and Selective Inhibitor of Mutant GTPase KRAS^G12C with Demonstrable CNS Penetration

Area of Science:

• Oncology
• Medicinal Chemistry
• Pharmacology

Background:

• The glycine to cysteine mutation at codon 12 of Kirsten rat sarcoma (KRAS) creates a druggable target.
• KRAS G12C-positive tumors represent a significant unmet medical need.
• Targeting oncogenic KRAS is a key strategy in cancer therapy.

Purpose of the Study:

• To report the structure-based drug design and optimization of AZD4747 (compound 14) as a clinical development candidate.
• To evaluate AZD4747 for the treatment of KRAS G12C-positive tumors, including central nervous system (CNS) metastases.
• To characterize the pharmacokinetic and pharmacodynamic properties of AZD4747, with a focus on CNS penetration.

Main Methods:

• Structure-based drug design utilizing a C5-tethered quinazoline scaffold.
• Lead optimization focusing on potency, drug metabolism and pharmacokinetics (DMPK), and brain penetration.
• Preclinical evaluation including in vitro assays and in vivo studies in various species.
• Positron Emission Tomography (PET) studies in primates to assess CNS exposure.

Main Results:

• Identification and optimization of AZD4747, a potent and selective inhibitor of KRAS G12C.
• Demonstration of brain penetrance and potential efficacy against CNS metastases.
• Observed species-specific differences in CNS exposure, resolved through primate PET studies.
• AZD4747 exhibits favorable predicted human pharmacokinetic properties, including low clearance and high oral bioavailability.

Conclusions:

• AZD4747 is a promising clinical development candidate for KRAS G12C-driven cancers.
• The drug's design ensures high confidence in CNS exposure, crucial for treating brain metastases.
• Preclinical data supports the potential of AZD4747 as an effective therapeutic agent in humans.