1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemECCG-203971Cat. No.: HY-108361CAS No.: 1443437-74-8分式: CHClNO分量: 408.88作靶點: Ras作通路: GPCR/G Protein儲存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數據體外實驗 DMSO : 155 mg/mL (379.08 mM)H2O : 40% PEG300 5% Twe

2、en-80 45% salineSolubility: 2.5 mg/mL (6.11 mM); Clear solution2. 請依序添加每種溶劑： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 2.5 mg/mL (6.11 mM); Suspended solution; Need ultrasonic1/3 Master of Small Molecules 您邊的抑制劑師www.MedChemE3. 請依序添加每種溶劑： 10% DMSO 90% corn oilSolubility: 2.5 mg/mL (6.11 mM); Cle

3、ar solutionBIOLOGICAL ACTIVITY物活性 CCG-203971第代 RhoA/肌相關轉錄因 A (MRTF-A) 抑制劑。CCG-203971 有效抑制 RhoA/C 激活的清反應元件 (SRE)-熒光素酶 (IC50=6.2 M)。IC50 & Target RhoA/MRTF-A 1體外研究 CCG-203971, a second-generation Ras homolog gene family, member A (RhoA)/myocardin-relatedtranscription factor A (MRTF-A)/serum response f

4、actor (SRF) pathway inhibitor, represses both matrix-stiffness and transforming growth factor betamediated fibrogenesis as determined by protein and geneexpression in a dose-dependent manner. CCG-203971 significantly represses TGF- induced MKL1expression at 25 M concentration 1. Human dermal fibrobl

5、asts are plated onto 96-well plates and allowedto grow for 3 days in the presence of 30 M CCG-203971 or DMSO vehicle. Viable cell density is assessedthrough enzymatic reduction of the water-soluble tetrazolium dye WST-1. Scleroderma dermal fibroblastsproliferate faster than normal cells, and this is

6、 inhibited by CCG-203971 2.體內研究 CCG-203971 is tested in a Bleomycin skin injury model. Bleomycin is administered in 50 L of DMSOintraperitoneally. Preliminary studies show that Bleomycin administered in this manner is well tolerated at 100mg/kg twice a day. Intradermal Bleomycin for 2 weeks along wi

7、th the DMSO control (50 L i.p.) results inmarked dermal thickening (P 2.PROTOCOLCell Assay 2 Human dermal fibroblasts (2.0104) are plated into a 96-well plate and grown overnight in DMEM containing10% FBS. Media are removed and replaced with DMEM containing 2% FBS and 30 M CCG-203971 or0.1% DMSO con

8、trol. After 72 hours WST-1 dye is added to each well, and after 60 minutes absorbance at490 nm is read using a Wallac Victor2 plate reader 2.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Mice 2Administration 2 Skin fibrosis is induced in C57BL/

9、6 mice (female, 8 weeks old) by local intracutaneous injection of 100 L ofBleomycin (1 mg/mL) in phosphate-buffered saline (PBS), every day for 2 weeks in a defined area (1 cm2)on the upper back. Intracutaneous injection of 100 L of PBS is used as a control. Three groups of mice witha total of 21 mi

10、ce are used. One group receives injections of PBS and the other two are challenged withBleomycin. Twice-a-day intraperitoneal administration of CCG-203971 (100 mg/kg in 50 L of DMSO) isinitiated together with the first challenge of Bleomycin and continues for 2 weeks. DMSO is used as thevehicle cont

11、rol. The three groups of animals are: (1) PBS/DMSO; (2) Bleomycin/DMSO; and (3)Bleomycin/CCG-203971. After treatment, animals are humanely killed by cervical dislocation, and tissue iscollected 2.2/3 Master of Small Molecules 您邊的抑制劑師www.MedChemEMCE has not independently confirmed the accuracy of the

12、se methods. They are for reference only.REFERENCES1. Johnson LA, et al. Novel Rho/MRTF/SRF inhibitors block matrix-stiffness and TGF-induced fibrogenesis in human colonicmyofibroblasts. Inflamm Bowel Dis. 2014 Jan;20(1):154-65.2. Haak AJ, et al. Targeting the myofibroblast genetic switch: inhibitors of myocardin-related transcription factor/serum response factor-regulated gene transcription prevent fibrosis in a murine model of skin injury. J Pharmacol Exp Ther. 2014 Jun;349(3):480-6.McePdfHeight