Optimization of Covalent 6-Cyanoquinazoline KRAS^G12C Inhibitors for the Treatment of Solid Tumors

Area of Science:

• Oncology
• Medicinal Chemistry
• Pharmacology

Background:

• The KRASG12C mutation is a key driver in various solid tumors, making it a significant therapeutic target.
• Covalent inhibitors targeting the KRASG12C cysteine-12 residue offer a promising strategy against this historically undruggable oncogene.

Purpose of the Study:

• To identify and optimize novel covalent irreversible inhibitors targeting the KRASG12C mutation.
• To develop a potent, orally bioavailable molecule with demonstrated antitumor activity and a projected human dose.

Main Methods:

• Structure-based drug design was employed to identify novel switch-II pocket-binding motifs.
• In silico models were used to predict metabolic stability and permeability.
• Lead optimization focused on maximizing covalent modification rates and ADME properties.

Main Results:

• Identification of 6-cyanoquinazoline covalent irreversible KRASG12C inhibitors.
• Discovery of potent, orally bioavailable lead molecule 13de.
• Demonstration of significant antitumor efficacy of 13de in a human lung adenocarcinoma xenograft model (NCI-H1373).

Conclusions:

• Molecule 13de represents a promising therapeutic candidate for KRASG12C-mutated solid tumors.
• Pharmacokinetic and efficacy studies support an estimated efficacious human dose of 192 mg once daily.
• This work advances the development of targeted therapies for KRASG12C-driven cancers.