CEP-40783
Names
[ CAS No. ]:
1437321-24-8
[ Name ]:
CEP-40783
[Synonym ]:
N-{4-[(6,7-Dimethoxy-4-quinolinyl)oxy]-3-fluorophenyl}-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxamide
5-Pyrimidinecarboxamide, N-[4-[(6,7-dimethoxy-4-quinolinyl)oxy]-3-fluorophenyl]-3-(4-fluorophenyl)-1,2,3,4-tetrahydro-1-(1-methylethyl)-2,4-dioxo-
Biological Activity
[Description]:
CEP-40783 is a potent, selective and orally available inhibitor of AXL and c-Met with IC50 values of 7 nM and 12 nM, respectively.
[Related Catalog]:
[Target]
IC50: 7 nM (AXL) and 12 nM (c-Met)[1]
[In Vitro]
In AXL-transfected 293GT cells, CEP-40783 is 27-fold more active compared to recombinant enzyme with an IC50 value of 0.26 nM. CEP-40783 also demonstrates superior activity against c-Met in GTL-16 cells (IC50=6 nM). The increased inhibitory activity of CEP-40783 in cells could be attributed to its extended residence time on both AXL and c-Met, consistent with a Type II mechanism. CEP-40783 shows high kinome selectivity against 298 kinases with an S90 of 0.04 (fraction of kinases showing >90% inhibition at 1 µM)[1].
[In Vivo]
CEP-40783 shows dose- and time-dependent inhibition of AXL phosphorylation using NCI-H1299 NSCL xenografts with 80% target inhibition at 0.3 mg/kg 6 h post dose and complete target inhibition to >90% inhibition at 1 mg/kg between 6-24 h, while a 10 mg/kg po dose resulted in complete AXL inhibition up to 48 h post dosing[1]. In 3/5 (60%) of the tumor models, CEP-40783 shows in vivo efficacy, including tumor regressions, significantly superior to that achieved with an optimal regimen of paclitaxel. In 4/4 (100%) of the erlotinib-insensitive tumor models, CEP-40783 demonstrates significant efficacy (66 to 118% TGI) compared to the control group at the 30 mg/kg dose. Additionally, CEP-40783 in combination with erlotinib demonstrate superior anti-tumor efficacy compared to CEP-40783 and erlotinib single agents in the one erlotinib-sensitive model evaluated. CEP-40783 as a single agent and in combination with erlotinib are well tolerated[2].
[Animal admin]
Mice: Mice bearing established Champions TumorGrafts are treated orally with 10 mg/kg and 30 mg/kg qd of CEP-40783 for 10 to 34 days and anti-tumor efficacy and tolerability are evaluated[2].
[References]
[Related Small Molecules]
Chemical & Physical Properties
[ Density]:
1.4±0.1 g/cm3
[ Molecular Formula ]:
C31H26F2N4O6
[ Molecular Weight ]:
588.558
[ Exact Mass ]:
588.182068
[ LogP ]:
5.35
[ Index of Refraction ]:
1.646
[ Storage condition ]:
-20℃