R547

• 产品号: S2688
• CAS号: 741713-40-6
• 分子式: C18H21F2N5O4S
• 分子量: 441.4522464
• 保 存: -20°C

产品别名

• 标题: R547
• IUPAC标准名: 5-(2,3-difluoro-6-methoxybenzoyl)-2-N-(1-methanesulfonylpiperidin-4-yl)pyrimidine-2,4-diamine
• IUPAC传统名: 5-(2,3-difluoro-6-methoxybenzoyl)-2-N-(1-methanesulfonylpiperidin-4-yl)pyrimidine-2,4-diamine

产品登记号

• CAS号: 741713-40-6

产品性质

• 作用靶点: CDK
• 成盐信息: Free Base
• 保存条件: -20°C

产品详细信息

详细说明 (English)

Biological Activity

• Description: R547 is a potent and selective CDK inhibitor with K_i and IC50 of 1-3 nM and 80 nM respectively.
• Targets: CDK
• IC50: 80 nM ^[2]
• In Vitro: R547 identified as a diaminopyrimidine compound, which is a potent and selective ATP-competitive CDK inhibitor. R547 effectively inhibits CDK1/cyclinB, CDK2/cyclinE, and CDK4/cyclinD1(Ki=1–3nM) and is inactive(Ki>5,000nM) against a panel of >120 unrelated kinases. R547 effectively inhibits the proliferation of tumor cell lines independent of multidrug resistant status, histologic type, retinoblastoma protein, or p53 status, with IC50s <0.60 μm.="" r547="" reduces="" phosphorylation="" of="" the="" cellular="" retinoblastoma="" protein="" at="" specific="" cdk="" phosphorylation="" sites="" at="" the="" same="" concentrations="" that="" induced="" cell="" cycle="" arrest,="" suggesting="" a="" potential="" pharmaco="" dynamics="" marker="" for="" clinical="" use.="" r547="" inhibits="" the="" proliferation="" of="" tumor="" cell="" lines="" and="" is="" active="" in="" all="" 19="" cell="" lines="" tested="" irrespective="" of="" tissue="" of="" origin,="" multidrug="" resistance="" (mdr),="" p53,="" or="" retinoblastoma="" status.="">^[1] R547 possessing both 5-and 6-fluoro substitution culminated in an Inhibitor with low, single-digit nanomolar potency against the CDKs(Ki=0.001,0.003,and 0.001 μM for CDK1,CDK2, and CDK4,respectively) and excellent cellular potency (IC50=0.08 μM,HCT116 cell line). ^[2]
• In Vivo: R547 administered with oral and i.v. dosing in multiple established human tumor significantly inhibits tumor activity(P < 0.01).="" r547="" administered="" orally="" at="" dose="" of="" 40="" mg/kg="" daily="" in="" colon,="" lung,="" breast,="" prostate,="" and="" melanoma="" human="" tumor="" xenograft="" models="" shows="" significant="" tgi="" (79–99%).="" r547="" is="" equally="" efficacious="" (tgi,="" 61–95%)="" when="" dosed="" with="" 40="" mg/kg="" i.v.="" once="" weekly.="" these="" doses="" of="" r547="" are="" not="" toxic="" and="" did="" not="" result="" in="" body="" weight="" loss.="" r547="" does="" not="" show="" signs="" of="" overt="" toxicity="" during="" the="" course="" of="" the="" 3-week="" study="" and="" any="" gross="" pathology="" at="" necropsies="" done="" at="" the="" end="" of="" the="" studies.="">^[1] R547 inhibits tumor growth up to 95% in the HCT116 human colorectal tumor xenograft model in nude mice . R547 causes significant TGI in all of the models tested when dosed orally and i.v. at or below the maximum tolerated dose. R547 inhibits phosphorylation of retinoblastoma protein in tumors at the efficacious exposures in tumor xenograft models, providing a pharmacodynamic biomarker for clinical use. R547 reported here suggests that this is a promising molecule for evaluation in the treatment of solid tumors. ^[2]
• Clinical Trials: R547 is currently in Phase I clinical trial for the treatment of cancer.

References

• References: [1] Rodriguez A , et al. Mol Cancer Ther, 2006, 5(11), 2644-2658.
• References: [2] Chu XJ, et al. J Med Chem, 2006, 49(22), 6549-6560.
• References: [3] Berkofsky-Fessler W, et al. Mol Cancer Ther, 2009, 8(9), 2517-2525.

参考文献

• Rodriguez A , et al. Mol Cancer Ther, 2006, 5(11), 2644-2658.
• Chu XJ, et al. J Med Chem, 2006, 49(22), 6549-6560.
• Berkofsky-Fessler W, et al. Mol Cancer Ther, 2009, 8(9), 2517-2525.