Saracatinib, Free Base **

产品名称：Saracatinib, Free Base
产品货号：LC  S-8906
产品规格：1 G
Saracatinib an orally available Src kinase inhibitor.
Saracatinib inhibits c-Src and Abl enzymes at low nanomolar concentrations.  Saracatinib blocked the tumor growth of a c-Src-transfected 3T3-fibroblast xenograft in vivo and increased significantly the survival of animals in a highly aggressive model of human pancreatic cancer.  Hennequin, L.F., et al.  "N-(5-chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5- (tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a novel, highly selective, orally available, dual-specific c-Src/Abl kinase inhibitor."  J. Med. Chem. 49:  6465-6488 (2006).
Saracatinib blocked the proliferation of various cell lines tested (IC50 = 0.2 - >10 µM) and inhibited tumor growth in 4/10 xenograft models tested.  Saracatinib had significant antimigratory and anti-invasive effects in vitro, and inhibited metastasis of bladder cancer in vivo.  Saracatinib blocked phosphorylation of Src substrates paxillin and FAK in both growth-inhibition-resistant and -sensitive xenografts.  Green, T.P., et al.  "Preclinical anticancer activity of the potent, oral Src inhibitor AZD0530."  Mol. Oncol. 3:  248-261 (2009).
Saracatinib blocked the growth of, and induced apoptosis in, chronic myeloid leukaemia (CML) and Ph+ acute lymphoblastic leukaemia (ALL) cells, but showed only slight effects on Ph- ALL cells.  Saracatinib overcame the resistance to imatinib due to the mutation Y253F in p185Bcr-Abl. Combination treatment of saracatinib and imatinib showed an additive inhibitory effect on the proliferation of CML BV173 cells but not on Ph+ ALL SupB15 cells.  Gwanmesia, P.M., et al.  "The effect of the dual Src/Abl kinase inhibitor AZD0530 on Philadelphia positive leukaemia cell lines."  BMC Cancer 9:  53 (2009).
Saracatinib inhibited the anchorage-dependent growth of MCF-7 with IC50 of 0.47 µM, which was increased 4-fold in the presence of estrogen.  In contrast, saracatinib inhibited the growth of cells stably expressing the mutant ERα with an elevated IC50 that was only increased 1.4-fold by estrogen stimulation.  The results indicated that c-Src inhibition is blocked by estrogen signaling.  Herynk, M.H., et al.  "Cooperative action of tamoxifen and c-Src inhibition in preventing the growth of estrogen receptor-positive human breast cancer cells."  Mol. Cancer Ther. 5:  3023-3031 (2006).
Saracatinib inhibited the proliferation of DU145 and PC3 prostate cancer cells, apparently by reducing binding of beta-catenin to the promoters of G1 phase cell cycle regulators cyclin D1 and c-Myc.  Saracatinib also decreased orthotopic DU145 xenograft growth by 45% in mice.  Chang, Y.M., et al.  "Src family kinase oncogenic potential and pathways in prostate cancer as revealed by AZD0530."  Oncogene 27:  6365-6375 (2008).
Saracatinib treatment is feasible and tolerable in previously treated patients suffering from advanced castration-resistant prostate cancer, but it had little clinical efficacy as monotherapy.  Lara, P.N. Jr., et al.  "A phase II trial of the Src-kinase inhibitor AZD0530 in patients with advanced castration-resistant prostate cancer: a California Cancer Consortium study."  Anticancer Drugs 20:  179-184 (2009).
Storage:  Store at or below -20 ºC.  Solubility:  Soluble in DMSO at 200 mg/mL; soluble in ethanol at 200 mg/mL with warming; very poorly soluble in water; maximum solubility in plain water is estimated to be about 20-100 µM; buffers, serum, or other additives may increase or decrease the aqueous solubility.  Disposal:  A

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