1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemERG2833Cat. No.: HY-16425CAS No.: 1215493-56-3Synonyms: RGFP109分式: CHNO分量: 339.43作靶點(diǎn): HDAC作通路: Cell Cycle/DNA Damage; Epigenetics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 (147

2、.31 mM)H2O : 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (7.37 mM); Clear solution2. 請(qǐng)依序添加每種溶劑： 10% DMSO 90% (20% SBE-CD in saline)1/3 Master of Small Molecules 您邊的抑制劑師www.MedChemESolubility: 2.5 mg/mL (7.37 mM); Clear solution3. 請(qǐng)依序添加每種溶劑： 10% DMSO 90% corn oilSolubility: 2.5 mg/mL (7.37

3、 mM); Clear solutionBIOLOGICAL ACTIVITY物活性 RG2833種腦滲透的 HDAC 抑制劑，抑制 HDAC1 和 HDAC3 的活性，IC50 值分別為 60 nM 和 50 nM。IC50 & Target HDAC3 HDAC150 nM (IC50) 60 nM (IC50)體外研究 The Ki values of RG2833 for HDAC1 and HDAC3 are 32 nM and 5 nM, respectively. RG2833 is highly activein the whole tested concentration r

4、ange from 1 to 10 M. Continuous incubation with RG2833 slows theincrease in frataxin protein, and when the compound is removed, frataxin protein levels rapidly increased inthe cells from patient P13 1. RG2833 produces significant increases in brain aconitase enzyme activity,together with reduction o

5、f neuronal pathology of the dorsal root ganglia (DRG) 2.體內(nèi)研究 RG2833 (150 mg/kg) is able to correct frataxin deficiency in the brain and heart of KIKI mice 24 hours after asingle injection, but not when lower doses are used. When followed in time, the frataxin mRNA increaseinduced by RG2833 in the KI

6、KI mouse can be first detected at 12 hours and reach a maximum at 24 hours inboth brain and heart 1. RG2833 (100 mg/kg, s.c.) is well tolerated in chronic dosing of mice without toxicity.RG2833 improves motor coordination of YG8R FRDA mice. RG2833 increases frataxin protein expression inthe brain of

7、 YG8R FRDA mice 2. RGFP109 (30 mg/kg, p.o. once daily for 6 days) has no acute effects ondyskinesia after single or 6 days once-daily treatment. One week following cessation of RGFP109,dyskinesia and duration of ON-time with disabling dyskinesia are reduced by 37% and 50%, respectively 3.PROTOCOLKin

8、ase Assay 2 Aconitase activities are determined by homogenization of mouse brain tissues on ice at 10% w/v in CellLyticMT Mammalian Tissue Lysis/Extraction buffer, followed by centrifugation at 800g for 10 min at 4C. Tissuelysates (50 L) are then added to 200 L of substrate mix (50 mM Tris/HCl pH 7.

9、4, 0.4 mM NADP, 5 mM Nacitrate, 0.6 mM MgCl2, 0.1% (v/v) Triton X-100 and 1U isocitrate dehydrogenase) and the reactions areincubated at 37C for 15 min, followed by spectrophotometric absorbance measurements every minute for15 min at 340 nm 37C to determine the reaction slope. Aconitase activities o

10、f mouse brain tissues are thennormalized to citrate synthase activities, which are determined using a citrate synthase assay kit.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Mice are housed in conventional open cages with Litaspen Premium 8/20

11、 bedding, paper wool nesting andAdministration 2 standard fun tunnel environmental enrichment, with 13 h light, 11 h dark, 20-23C and 45-60% humidity. Themice are given a diet of SDS RM3 Expanded food pellets and standard drinking water. Mice are givensubcutaneous injections of 150 mg/kg RG2833 thre

12、e times per week for 4.5 months, or 50 mg/kg 136 or 100mg/kg RG2833 five times per week for 5 months, followed by culling for tissue collection 24 h after the final2/3 Master of Small Molecules 您邊的抑制劑師www.MedChemEinjection.MCE has not independently confirmed the accuracy of these methods. They are f

13、or reference only.戶使本產(chǎn)品發(fā)表的科研獻(xiàn) J Mol Med (Berl). 2019 Jun 14. ACS Med Chem Lett. 2015 Jun 22;6(8):948-52. PLoS One. 2016 Apr 14;11(4):e0153574.See more customer validations on HYPERLINK / www.MedChemEREFERENCES1. Rai M, et al. Two new pimelic diphenylamide HDAC inhibitors induce sustained frataxin up

14、regulation in cells from Friedreichs ataxiapatients and in a mouse model. PLoS One. 2010, 5(1), e8825.2. Sandi C, et al. Prolonged treatment with pimelic o-aminobenzamide HDAC inhibitors ameliorates the disease phenotype of a Friedreichataxia mouse model. Neurobiol Dis. 2011, 42(3), 496-505.3. Johnston TH, et al. RGFP109, a histone deacetylase inhibitor attenuates L-DOPA-induced dyskinesia in the MPTP-lesioned marmoset:a proof-of-concept study. Parkinsonism Relat Disord. 201