RGB-286638-free-base - CDK 抑制劑 - 生命科學試劑 - MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemERGB-286638 free baseCat. No.: HY-15504ACAS No.: 784210-88-4分式: CHNO分量: 545.63作靶點: CDK; GSK-3; MEK; JAK作通路: Cell Cycle/DNA Damage; PI3K/Akt/mTOR; Stem Cell/Wnt;MAPK/ERK Pathway; Epigenetics; JAK/STAT Signaling儲存式: Powder -20C 3 y

2、ears4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數(shù)據(jù)體外實驗 DMSO : 36 mg/mL (65.98 mM)* means soluble, but saturation unknown.Mass Solvent1 mg 5 mg 10 mg Concentration制備儲備液1 mM 1.8327 mL 9.1637 mL 18.3274 mL5 mM 0.3665 mL 1.8327 mL 3.6655 mL10 mM 0.1833 mL 0.9164 mL 1.8327 mL請根據(jù)產(chǎn)品在不同溶劑中的溶解度，選擇合適的溶劑配

3、制儲備液，并請注意儲備液的保存式和期限。BIOLOGICAL ACTIVITY物活性 RGB-286638種有效的 CDK 抑制劑，抑制 cyclin T1-CDK9，cyclin B1-CDK1，cyclin E-CDK2，cyclin D1-CDK4，cyclin E-CDK3 和 p35-CDK5 活性，IC50 分別為 1，2，3，4，5 和 5 nM；同時可抑制 GSK-3，TAK1，Jak2 和 MEK1，IC50 值分別為 3，5，50，和 54 nM。IC50 & Target T1-CDK9 cyclin B1-CDK1 cyclin E-CDK2 cyclin D1-CDK

4、41/3 Master of Small Molecules 您邊的抑制劑師www.MedChemE1 nM (IC50) 2 nM (IC50) 3 nM (IC50) 4 nM (IC50)cyclin E-CDK3 p35-CDK5 cyclin H-CDK7 cyclin D3-CDK65 nM (IC50) 5 nM (IC50) 44 nM (IC50) 55 nM (IC50)GSK-3 JAK2 MEK1 Fms3 nM (IC50) 50 nM (IC50) 54 nM (IC50) 1 nM (IC50)TAK1 JNK1a1 JNK1a2 C-src5 nM (IC50)

5、 17 nM (IC50) 40 nM (IC50) 25 nM (IC50)AMPK41 nM (IC50)體外研究 RGB-286638 is an indenopyrazole-derived CDK inhibitor (CDKI) with Ki-nanomolar activity againsttranscriptional CDKs. RGB-286638 inhibits several tyrosine and serine/threonine non-CDK enzymes, i.e.GSK-3, TAK1, AMPK, Jak2, MEK1. The dose- and

6、 time-dependent effect of treatment with RGB-286638(12.5-100nM) is investigated on the growth of human p53-wt (MM.1S, MM.1R, and H929) and p53-mutant(U266, OPM1, and RPMI) MM cells by MTT assay, assessing viability at 24 and 48 hours. The half-maximally effective concentrations (EC50) range between

7、20 and 70 nM at 48 hours. Dose-dependentdifferences in growth among p53-wt and -mutant cells are observed after 50nM treatment, with p53-wtMM.1S, MM.1R and H929 being slightly more sensitive to RGB-286638 treatment at 48h 1.體內(nèi)研究 Dose-finding studies with RGB-286638 identify 40 mg/kg/day IV treatment

8、 as the maximum tolerated dose inSCID mice. Five days IV treatment with RGB-286638 significantly suppresses MM tumor growth, withmaximum TGI (%) noted at day 14 following end of treatment at 85.06% and 86.34% in the 30 mg/kg and 40mg/kg treated cohorts respectively. The log10 cell kill (LCK Td: 4.5

9、days) is 1.6 for both treated groups. RGB-286638 treatment is also associated with improved survival, evidenced by first death at day 24 in controlsversus day 43 in both treated groups. No toxic deaths occurred during this study: maximum percentage ofbody weight (BW) loss is observed on day 5 (8.4%)

10、 at 30 mg/kg dosage schedule, and on day 15 (9.9%)after 40 mg/kg dosing, with weight recovery in the following two weeks 1.PROTOCOLKinase Assay 1 Nuclear proteins are isolated from MM.1S cells treated with 50nM RGB-286638 for 1, 4, and 8 h, usingNuclear Extraction Kit. Nuclear protein aliquots are a

11、dded to the 96-well plate coated with specific double-stranded DNA sequence containing the p53 response element for overnight incubation. p53 in the nuclearextract is detected by addition of a specific primary antibody directed against p53. A secondary antibodyconjugated to HRP is added to provide a

12、 sensitive colorimetric readout at 450 nm. All experiments areperformed in triplicates 1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Cell Assay 1 Colorimetric assays are performed to assay drug activity at increasing concentrations of RGB-286638 (0-

13、100nM). Expressing wild-type p53 (MM.1S, MM.1R, H929) or mutant-p53 (U266, OPM1, RPMI) cells from2/3 Master of Small Molecules 您邊的抑制劑師www.MedChemE24- or 48-h cultures are pulsed with 10L of 5mg/mL MTT to each well, followed by incubation at 37C for 4h,and addition of 100 L isopropanol containing 0.0

14、4 HCl. Absorbance readings at a wavelength of 570nm(with correction using readings at 630nm) are taken on a spectrophotometer. All experiments are performedin triplicates 1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Mice 1Administration 1 Th

15、e in vivo anti-MM activity of RGB-286638 is evaluated in an MM xenograft model. RGB-286638 dosingsolutions of 2 and 3 mg/mL in 5% dextrose/water (D5W) pH5.2, as well as D5W pH5.2 for vehicle controldosing group, are prepared and provided by Agennix AG. CB-17 severe combined immunodeficient (SCID)mic

16、e are used. Forty male 5-6 week old mice are irradiated (2 Gy 200 rad) using cesium 137 (137Cs)-irradiator source); 24h after irradiation, 2.5106 MM.1S cells are inoculated subcutaneously in the upperback. When tumor weight is approximately 100 mg, mice are randomly assigned into 3 cohorts receiving

17、daily IV tail vein injections for 5 consecutive days with either RGB-286638 30 mg/kg (8 mice), 40 mg/kg (9mice), or control vehicle alone (10 mice). Animals are monitored for body weight and tumor volume by calipermeasurements every alternate day. Tumor volume is estimated. Survival is evaluated fro

18、m the first day oftreatment until death. Tumor growth is evaluated using caliper measurements from the first day of treatmentuntil day of first sacrifice. Percentage tumor growth inhibition (TGI) is calculated.MCE has not independently confirmed the accuracy of these methods. They are for reference only.戶使本產(chǎn)品發(fā)表的科研獻 Science. 2017 Dec 1;358(6367).See more customer validations on HYPERLINK / www.MedChemEREFERENCES1. Cirstea D, et al. Small-molecule multi-targeted kinase inhibitor RGB-286638 triggers P53-dependent and -independent anti-multiplemyeloma ac