Discovery of D6808, a Highly Selective and Potent Macrocyclic c-Met Inhibitor for Gastric Cancer Harboring <i>MET</i> Gene Alteration Treatment

Abstract

<i>MET</i> alterations have been validated as a driven factor in NSCLC and gastric cancers. The c-Met inhibitors, capmatinib, tepotinib, and savolitinib, are only approved for the treatment of NSCLC harboring exon 14 skipping mutant MET. We used a molecular hybridization in conjunction with macrocyclization strategy for structural optimization to obtain a series of 2-(2-(quinolin-6-yl)ethyl)pyridazin-3(2<i>H</i>)-one derivatives as new c-Met inhibitors. One of the macrocyclic compounds, D6808, potently inhibited c-Met kinase and <i>MET</i>-amplified Hs746T gastric cancer cells with IC₅₀ values of 2.9 and 0.7 nM, respectively. It also strongly suppressed Ba/F3-Tpr-Met cells harboring resistance-relevant mutations (F1200L/M1250T/H1094Y/F1200I/L1195V) with IC₅₀ values of 4.2, 3.2, 1.0, 39.0, and 33.4 nM, respectively. Furthermore, D6808 exhibited extraordinary target specificity in a Kinome profiling against 373 wild-type kinases and served as a promising macrocycle-based compound for further anticancer drug development.