CGI-1746 - Btk 抑制劑 - 生命科學(xué)試劑 - MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemECGI-1746Cat. No.: HY-11999CAS No.: 910232-84-7分式: CHNO分量: 579.69作靶點(diǎn): Btk; Autophagy作通路: Protein Tyrosine Kinase/RTK; Autophagy儲(chǔ)存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數(shù)據(jù)體外實(shí)驗(yàn) DMSO : 50 mg/mL (86.25

2、 mM)H2O : 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (4.31 mM); Clear solution2. 請(qǐng)依序添加每種溶劑： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 2.5 mg/mL (4.31 mM); Suspended solution; Need ultrasonic1/3 Master of Small Molecules 您邊的抑制劑師www.MedChemE3. 請(qǐng)依序添加每種溶劑： 10% DMSO 90% corn oilSolubilit

3、y: 2.5 mg/mL (4.31 mM); Suspended solutionBIOLOGICAL ACTIVITY物活性 CGI-1746種有效的，選擇性的 Btk 抑制劑，IC50 值為 1.9 nM。IC50 & Target IC50: 1.9 nM (Btk)體外研究 CGI1746 is specific for Btk, with appr 1,000-fold selectivity over Tec and Src family kinases. In an ATP-freecompetition binding assay, the dissociation cons

4、tant for Btk is 1.5 nM. CGI1746 inhibits Btk activity in a newbinding mode that stabilizes an inactive nonphosphorylated enzyme conformation. CGI1746 inhibits bothauto- and transphosphorylation steps necessary for enzyme activation. CGI1746 completely inhibits anti-IgM-induced murine and human B cel

5、l proliferation, with IC50s of 134 nM and 42 nM, respectively, but has noeffect on anti-CD3- and anti-CD28-induced T cell proliferation. CGI1746 potently inhibits the proliferation ofCD27+IgG+ B cells isolated from the tonsils of four human donors with an average IC50 of 112 nM. Inmacrophages, CGI17

6、46 abolishes FcRIII-induced TNF, IL-1 and IL-6 production. CGI1746 potentlyinhibits TNF, IL-1 and, to a lesser extent, IL-6 (three- to eight-fold higher IC50) production in humanmonocytes stimulated with immobilized or soluble immune complexes 1. CGI-1746 does not kill cells as wellas the irreversib

7、le BTK inhibitors at the same drug concentration. CGI-1746 significantly reducesphosphorylation of both the BTK-A and BTK-C proteins, indicating the auto-phosphorylation of the BTK-Cisoform is inhibited in a manner similar to BTK-A. CGI-1746 does not kill LNCaP or DU145 prostate cancercells at the s

8、ame concentrations as Ibrutinib or AVL-292, but it demonstrates similar inhibition of BTKphosphorylation at tyrosine 233 in the SH3 domain 2.體內(nèi)研究 CGI1746 abrogates B cell-dependent arthritis. CGI1746 treatment (100 mg/kg, s.c, twice-daily dosing) resultsin significant inhibition (97%) of overall cli

9、nical arthritis scores. CGI1746 treatment substantially reduces TNF, IL-1 and IL-6, as well as MCP1 and MIP-1 on both the mRNA and protein level in the passive anti-collagen II antibody-induced arthritis (CAIA) model. CGI1746 shows comparable efficacy to TNF blockadeand significantly reduces clinica

10、l scores, as well as joint inflammation, in mice or rats with established arthritis1.PROTOCOLCell Assay 2 5103 DU145 cells or 104 LNCaP cells per well, grown on 96 well plates for 24h, are treated with 1 to 30 MBTK inhibitors. Cells are fixed after 72h with 2.5% formaldehyde, and stained with Hoechs

11、t 33342. Controlcells are treated with DMSO. Cell images are acquired using an IN Cell Analyzer 2200 high content imagingsystem, with a 20X objective. At least 9 fields are imaged per single well of each experiment. Cell numbersare determined and statistics performed using IN Cell Investigator 3.4 h

12、igh content image analysis software.Each experiment is replicated 3 times, and data are presented as meanSD. Results are consideredsignificant if p 0.05.MCE has not independently confirmed the accuracy of these methods. They are for reference only.2/3 Master of Small Molecules 您邊的抑制劑師www.MedChemE戶使本

13、產(chǎn)品發(fā)表的科研獻(xiàn) Mol Pharmacol. 2017 Mar;91(3):208-219. J Biomol Screen. 2015 Aug;20(7):876-86. Patent. US20190040013A1.See more customer validations on HYPERLINK / www.MedChemEREFERENCES1. Di Paolo, Julie A. et al. Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis. Nature Chemical Biology (2011),7(1), 41-502. Kokabee L, et al. Brutons tyrosine kinase is a potential therapeutic target in prostate cancer. Cancer Biol Ther. 2015;16(11):1604-15