product name (S)-crizotinib
Description: (S)-crizotinib, the (S)-enantiomer of crizotinib, is a novel and potent MTH1 (NUDT1) inhibitor with IC50 of 72 nM in a cell-free assay. It efficiently inhibited colony formation of SW480 cells andKRAS-mutated PANC1 cells, similar to SCH51344. In addition, in vitro Kd measurements indicated that (S)-crizotinib was considerably less potent than the (R)-enantiomer against the established targets ALK,MET and ROS1. (S)-crizotinib did not lead to the detection of any significant effects on proliferation in SW480 cells and showed highest toxicity towards the SV40T and KRASV12 cells.
References: Nature. 2014 Apr 10;508(7495):222-7.
450.34
Formula
C21H22Cl2FN5O
CAS No.
1374356-45-2
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 42 mg/mL (93.3 mM)
Water: <1 mg/mL
Ethanol: 22 mg/mL (48.9 mM)
Solubility (In vivo)
Synonyms
other peoduct :
| In Vitro |
In vitro activity: (S)-crizotinib disrupts nucleotide pool homeostasis via MTH1 inhibition, induces an increase in DNA single-strand breaks, and activates DNA repair in human colon carcinoma cells. Kinase Assay: Half-maximal inhibitory concentrations (IC50) are determined using a luminescence-based assay with some minor modifications. Briefly, serial dilutions of compounds are dissolved in assay buffer (100 mM Tris-acetate pH 7.5, 40 mM NaCl and 10 mM Mg(OAc)2 containing 0.005% Tween-20 and 2 mM dithiothreitol (DTT). Upon addition of MTH1 recombinant protein (final concentration 2 nM), plates are incubated on a plate shaker for 15 min at room temperature. After addition of the substrate dGTP (final concentration 100 µM), 8-oxo-dGTP (final concentration 13.2 µM), or 2-OH-dATP (final concentration 8.3 µM) the generation of pyrophosphate (PPi) as a result of nucleotide triphosphate hydrolysis by MTH1 is monitored over a time course of 15 min using the PPi Light Inorganic Pyrophosphate Assay kit. IC50 values are determined by fitting a dose-response curve to the data points using nonlinear regression analysis using the GraphPad Prism software. Cell Assay: One day before treatment, cells are seeded per well in six-well plates and incubated for 24 h. The next day DMSO (equal to highest amount of compound dilution, maximum 0.2%) or compounds in increasing concentrations were added and cells incubated at 37 °C, 5% CO2, for 7-10 days. After washing with PBS, cells are fixed with ice-cold methanol, stained with crystal violet solution (0.5% in 25% methanol) and left to dry overnight. For quantification of results, ultraviolet absorbance of crystal violet is determined at 595 nm following solubilisation by 70% ethanol. Data are analysed using nonlinear regression analysis using the GraphPad Prism software. |
|---|---|
| In Vivo | (S)-Crizotinib (50 mg/kg, orally, daily) impairs tumor growth in an SW480 colon carcinoma xenograft model |
| Animal model | SW480 colon carcinoma xenograft mouse model. |
| Formulation & Dosage | Formulated in 1% DMSO, 10% ethanol, 10% Cremophor, 10% Tween 80, 69% PBS; 50 mg/kg daily; p.o. |
| References | Nature. 2014 Apr 10;508(7495):222-7. |
