Synthesis and c-Met Kinase Inhibition of 3,5-Disubstituted and 3,5,7-Trisubstituted Quinolines: Identification of 3-(4-Acetylpiperazin-1-yl)-5-(3-nitrobenzylamino)-7- (trifluoromethyl)quinoline as a Novel Anticancer Agent

Abstract

By use of an improved synthetic strategy, a series of 3,5-disubstituted and 3,5,7-trisubstituted quinolines were readily prepared. 3,5,7-Trisubstituted quinolines 21a-c, 21l, and 27a-c were identified as the most potent c-Met inhibitors with IC(50) of less than 1.0 nM. Compound 21b showed the most promising overall PK profile and has high potency and extraordinary selectivity to c-Met against c-Met family member Ron and 12 other tyrosine kinases. It produced constitutive inhibition of c-Met phosphorylation in c-Met dependent cell lines. At doses of 100 mg/kg, compound 21b showed statistically significant tumor growth inhibition (68-69%) in both NIH-3T3-TPR-Met and U-87 MG human gliobastoma xenograft models. These results clearly indicated that compound 21b is a potent and highly selective c-Met inhibitor. Its favorable in vitro and in vivo profiles warrant further investigation.

SOMG-833, a Novel Selective c-MET Inhibitor, Blocks c-MET–Dependent Neoplastic Effects and Exerts Antitumor Activity

“…In fact, recent clinical trials of c-MET pathway-targeted agents have yielded convincing evidence for the benefit of targeting c-MET in cancer therapy, including monotherapy and combined therapy (Sequist et al, 2011;Bendell et al, 2013). Previously, we conducted a screen to discover specific c-MET inhibitors, and SOMG-833 was selected for further characterization of c-MET-targeting antitumor efficacy (Wang et al, 2011). …”

“…Compounds SOMG-833 was synthesized at Shanghai Institute of Material Medica, Chinese Academy of Sciences (Shanghai, China) as we have reported previously (Wang et al, 2011). This compound was fully characterized and possessed a purity of 99%.…”

“…SOMG-833 was initially identified as a potent small-molecule inhibitor of c-MET with an IC 50 of 0.93 6 0.15 nM in a biochemical enzymatic assay ( Fig. 1A) (Wang et al, 2011). We were prompted to investigate whether this potency was specifically against c-MET.…”

Discovery and SAR study of c-Met kinase inhibitors bearing an 3-amino-benzo[d]isoxazole or 3-aminoindazole scaffold

“…We then evaluated the inhibitory effects of these compounds on the cell proliferation by using the protocol we previously reported. 47,48 As shown in Table 4, in the c-Met addicted NSCLC EBC-1 cells, seven compounds (12, 28a-d, 28f and 28h) outperformed the other counterparts with significant antiproliferative effects (IC 50 s less than 1 µM). However, these compounds suffered from a significant decrease in enzyme-tocell shift, likely due to their poor cellular penetration.…”

“…47,48 Compound 1 and panatinib were used as the reference compounds 28,31 for c-Met and VEGFR2 respectively. As shown in Fig.…”