Structure–activity relationship study of novel quinazoline-based 1,6-naphthyridinones as MET inhibitors with potent antitumor efficacy

Abstract As a privileged scaffold, the quinazoline ring is widely used in the development of EGFR inhibitors, while few quinazoline-based MET inhibitors are reported. In our ongoing efforts to develop new MET-targeted anticancer drug candidates, a series of quinazoline-based 1,6-naphthyridinone derivatives were designed, synthesized, and evaluated for their biological activities. The preliminary SARs studies indicate that the quinazoline scaffold was also acceptable for the block A of class II MET inhibitors. The further pharmacokinetic studies led to the identification of the most promising compound 22a with favorable in vitro potency (MET, IC50 = 9.0 nM), human microsomal metabolic stability (t1/2 = 621.2 min) and oral bioavailability (F = 42%). Moreover, 22a displayed good in vivo antitumor efficacy (IR of 81% in 75 mg/kg) in MET-positive human glioblastoma U-87 MG xenograft model. These positive results indicated that 22a is a potential new MET-targeted antitumor drug lead, which is worthy of further development.