c-Met-IN-14

c-Met-IN-14 (compound 26af) is a selective inhibitor of c-Met kinase from N-sulfonylamidine-based derivatives, with an IC50 value of 2.89 nM. c-Met-IN-14 shows anticancer activity by blocking phosphorylation of c-Met, and arrests cell cycle at G2/M phase. c-Met-IN-14 induces apoptosis of A549 cells in a dose-dependent manner[1].

Signaling Pathways >> Apoptosis >> Apoptosis

Research Areas >> Cancer

Signaling Pathways >> Protein Tyrosine Kinase/RTK >> FLT3

Signaling Pathways >> Protein Tyrosine Kinase/RTK >> c-Kit

Signaling Pathways >> Protein Tyrosine Kinase/RTK >> c-Met/HGFR

c-Met:2.89 nM (IC50)

c-Met-IN-14 (compound 26af) is a relatively selective inhibitor of c-Met kinase (IC50=2.89 nM), because of high inhibitory effects against c-Kit (IC50=4.26 nM) and Flt-3 (IC50=7.28 nM)[1]. c-Met-IN-14 (0.28-0.72 μM; 24 h) exhibits the remarkable anti-proliferative activities against cancer cell lines (A549, HT-29, MKN-45 and MDA-MB-231), with IC50s of 0.28-0.72 μM[1]. c-Met-IN-14 (0.25, 0.5, and 1.0 μM; 12 h) induces the late apoptotic and early apoptotic and (0.25, 0.5, and 1.0 μM; 24 h) shows anti-proliferative of A549 cells by arresting cell cycle at G2/M phase and apoptosis induction[1]. c-Met-IN-14 (1.35, or 6.12 μM, respectively; 24 h) has moderate selectivity towards cancer cells over normal cells, with the selectivity index of 4.2 and 19.1 to HUVEC (IC50=1.35 μM) and FHC cells (IC50=6.12 μM), respectively[1]. Western Blot Analysis[1] Cell Line: A549 Concentration: 0, 2, 4, 8 μM Incubation Time: 6 hours Result: Showed excellent inhibition against c-Met phosphorylation in a concentration-dependent manner.

c-Met-IN-14 (compound 26af) (p.o.; 8 mg/kg) exhibits safety profile and favorable pharmacokinetic properties in BALB/c mouse, with rapid absorption (Tmax=2.5 h), high maximum concentration (Cmax=1228.4 ng/mL), high plasma exposure (AUC0-∞=6.8 µg.h.mL-1), accepted elimination half-life (T1/2=3.5 h), and well clearance (1.18 L.h-1.kg-1), has a moderate oral bioavailability (74%) in mouse[1]. c-Met-IN-14 (i.p.; below 200 mg/kg) doesn’t cause abnormalities, anaphylactic responses, allergic reactions on mice[1]. Animal Model: 8-week-old male BALB/c mice [1] Dosage: 0 (vehicle), 100, 200, 300, or 400 mg/kg Administration: Intraperitoneal injection; treatment on day 0 and assessment every 3 days for 15 days Result: Showed no obvious toxicity in acute toxicity tests. Animal Model: Pharmacokinetic profiles of compound 26af in BALB/c mouse[1] Dosage: Administration: Result: Route Dose (mg/kg) T1/2 (h) Cmax (ng.mL-1) Tmax (h) AUC0-∞ (μg.h.mL-1) CL (L.h-1.kg-1) CL (%) i.v. 2 1.8 675.6 - 2.3 - p.o. 8 3.5 1228.4 2.5 6.8 1.18 74

[1]. Nan X, et al. Design, synthesis and biological evaluation of novel N-sulfonylamidine-based derivatives as c-Met inhibitors via Cu-catalyzed three-component reaction. Eur J Med Chem. 2020 Aug 15. 200:112470.