The ability of CH-223191 to compete with TCDD for binding to the AhR was assessed by incubating aliquots of cytosol prepared from untreated Hepa cells (2.1–2.5 mg protein/ml) with CH-223191 or flavone and [3H]TCDD at 3 nM for 2 h at room temperature. This concentration of TCDD is nonsaturating at these protein concentrations. Specific binding of [3H]TCDD was determined in duplicate aliquots by the hydroxylapatite assay(Gasiewicz and Neal, 1982), with correction for nonspecific binding measured in the presence of 150-fold excess of unlabeled 2,3,7,8-tetrachlorodibenzofuran. Data were expressed for each antagonist concentration as a percentage of the specific binding of [3H]TCDD in the absence of competitor.[1]
SMILES
O=C(C1=CC=NN1C)NC2=CC=C(/N=N/C3=CC=CC=C3C)C=C2C
靶点
Aryl Hydrocarbon Receptor(AhR)
动物实验
Male ICR mice (6 weeks old) were given oral vehicle (corn oil) or CH-223191 (10 mg/kg in corn oil) once a day for 25 days and treated i.p. with TCDD (100 g/kg in corn oil) once after the first week of CH-223191 treatment. The body weights of all mice were measured before dosing and at termination.[1]
数据来源文献
[1] Kim SH, et al. Mol Pharmacol. 2006, 69(6), 1871-1878. [2] Gramatzki D, et al. Oncogene. 2009, 28(28), 2593-2605. [3] Xie HQ, et al. Environ Health Perspect. 2013, 121(5), 613-618. [4] de Souza AR, et al. Toxicol Sci. 2014, 140(1), 204-223.
CH5183284 is a selective and orally available FGFR inhibitor with IC50 of 9.3 nM, 7.6 nM, 22 nM, and 290 nM for FGFR1, FGFR2, FGFR3, and FGFR4, respectively. Phase 1.
纯度
98%
储存/保存方法
Store at -20℃ for one year(Powder);Store at 2-4℃ for two weeks;Store at -20℃ for six months after dissolution.
基本信息
可溶性/溶解性
DMSO:71 mg/mL (199.22 mM)
生物活性
靶点
FGFR2 ,FGFR1 ,FGFR3 ,FGFR4
In vitro(体外研究)
In cell-based assay, CH5183284 prevents autophosphorylation of FGFR1, FGFR2, and FGFR3 at 100 to 300 nM in the DMS114 (FGFR1 amplification), SNU-16 (FGFR2 amplification), and KMS11 cell lines. CH5183284 thus produces selective antiproliferative activity against cancer cell lines harboring genetic alterations in FGFR. CH5183284 also inhibit FGFR2 harboring one type of the gatekeeper mutation (V564F) that causes resistance to other FGFR inhibitors.
In vivo(体内研究)
CH5183284 (100 mg/kg/day, p.o.) shows selective and significant antitumor activity against xenografts with FGFR genetic alterations such as KG1 (leukemia, FGFR1OP-FGFR1 fusion), SNU-16 (gastric cancer, FGFR2 amplification), MFE-280 (endometrial cancer, FGFR2 S252W mutation), UM-UC-14 (bladder cancer, FGFR3 S249C mutation), and RT112/84 (bladder cancer, FGFR3-TACC3 fusion).
参考文献
参考文献
1. Nakanishi Y, et al. Mol Cancer Ther. 2014, 13(11), 2547-2558.
[1]. Tanaka H, et al. The selective class I PI3K inhibitor CH5132799 targets human cancers harboring oncogenic PIK3CA mutations. Clin Cancer Res, 2011, 17(10), 3272-3281. [2]. Ohwada J, et al. Discovery and biological activity of a novel class I PI3K inhibitor, CH5132799. Bioorg Med Chem Leff, 2011, 21(6), 1767-1772