RGB-286638

CDKs inhibitor CAS# 784210-87-3

RGB-286638

Catalog No. BCC5519----Order now to get a substantial discount!

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Quality Control of RGB-286638

Number of papers citing our products

Chemical structure

RGB-286638

3D structure

Chemical Properties of RGB-286638

Cas No. 784210-87-3 SDF Download SDF
PubChem ID 11285001 Appearance Powder
Formula C29H37Cl2N7O4 M.Wt 618.55
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : ≥ 150 mg/mL (242.50 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name 1-[3-[4-[[4-(2-methoxyethyl)piperazin-1-yl]methyl]phenyl]-4-oxo-1H-indeno[1,2-c]pyrazol-5-yl]-3-morpholin-4-ylurea;dihydrochloride
SMILES COCCN1CCN(CC1)CC2=CC=C(C=C2)C3=NNC4=C3C(=O)C5=C4C=CC=C5NC(=O)NN6CCOCC6.Cl.Cl
Standard InChIKey WJVMGQMXUBAAPL-UHFFFAOYSA-N
Standard InChI InChI=1S/C29H35N7O4.2ClH/c1-39-16-13-34-9-11-35(12-10-34)19-20-5-7-21(8-6-20)26-25-27(32-31-26)22-3-2-4-23(24(22)28(25)37)30-29(38)33-36-14-17-40-18-15-36;;/h2-8H,9-19H2,1H3,(H,31,32)(H2,30,33,38);2*1H
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of RGB-286638

DescriptionRGB-286638 is a CDK inhibitor that inhibits the kinase activity of cyclin T1-CDK9, cyclin B1-CDK1, cyclin E-CDK2, cyclin D1-CDK4, cyclin E-CDK3, and p35-CDK5 with IC50s of 1, 2, 3, 4, 5 and 5 nM, respectively; also inhibits GSK-3β, TAK1, Jak2 and MEK1, with IC50s of 3, 5, 50, and 54 nM.In Vitro:RGB-286638 is an indenopyrazole-derived CDK inhibitor (CDKI) with Ki-nanomolar activity against transcriptional CDKs. RGB-286638 inhibits several tyrosine and serine/threonine non-CDK enzymes, i.e. GSK-3β, TAK1, AMPK, Jak2, MEK1. The dose- and 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 20 and 70 nM at 48 hours. Dose-dependent differences in growth among p53-wt and -mutant cells are observed after 50nM treatment, with p53-wt MM.1S, MM.1R and H929 being slightly more sensitive to RGB-286638 treatment at 48h[1].In Vivo:Dose-finding studies with RGB-286638 identify 40 mg/kg/day IV treatment as the maximum tolerated dose in SCID mice. Five days IV treatment with RGB-286638 significantly suppresses MM tumor growth, with maximum TGI (%) noted at day 14 following end of treatment at 85.06% and 86.34% in the 30 mg/kg and 40 mg/kg treated cohorts respectively. The log10 cell kill (LCK Td: 4.5 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 controls versus day 43 in both treated groups. No toxic deaths occurred during this study: maximum percentage of body weight (BW) loss is observed on day 5 (8.4%) 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].

References:
[1]. Cirstea D, et al. Small-molecule multi-targeted kinase inhibitor RGB-286638 triggers P53-dependent and -independent anti-multiple myeloma activity through inhibition of transcriptional CDKs. Leukemia. 2013 Dec;27(12):2366-75.

Protocol

Cell experiment [1]:

Cell lines

p53-wt (MM.1S) and p53-mutant (U266) cells

Preparation method

Limited solubility. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

12 and 24 h

Applications

50nM RGB-286638 treatment decreases cyclins (A, B1, D1, and D3), CDK1 and CDK4 expression in MM.1S cells, and reduces cyclin A and D1 levels slightly in U266 cells within 8h. 50nM RGB-286638 also reduces the expression of the anti-apoptotic proteins Mcl-1 and XIAP. Caspase-8, -9, -3 and PARP cleavage occurs within 4h in both MM.1S and U266 cell lines. Moreover, RGB-286638 causes cell cycle arrest and apoptosis in both cell lines.

Animal experiment [1]:

Animal models

Multiple myeloma xenograft mice

Dosage form

Daily IV tail vein injections for 5 consecutive days with either RGB-286638 30mg/kg (8 mice), 40mg/kg (9 mice)

Preparation method

2 and 3 mg/ml in 5% dextrose/water (D5W) pH5.2.

Application

RGB-286638 significantly inhibits MM tumor growth, with maximum TGI (%) noted at day 14 following end of treatment at 85.06% and 86.34% in the 30 mg/kg and 40 mg/kg treated cohorts respectively. RGB-286638 treatment also exhibits improved survival, evidenced by first death at day 24 in controls versus day 43 in both treated groups.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

1. Cirstea D, Hideshima T, Santo L et al. Small-molecule multi-targeted kinase inhibitor RGB-286638 triggers P53-dependent and -independent anti-multiple myeloma activity through inhibition of transcriptional CDKs. Leukemia. 2013 Dec;27(12):2366-75.

RGB-286638 Dilution Calculator

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RGB-286638 Molarity Calculator

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Preparing Stock Solutions of RGB-286638

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.6167 mL 8.0834 mL 16.1668 mL 32.3337 mL 40.4171 mL
5 mM 0.3233 mL 1.6167 mL 3.2334 mL 6.4667 mL 8.0834 mL
10 mM 0.1617 mL 0.8083 mL 1.6167 mL 3.2334 mL 4.0417 mL
50 mM 0.0323 mL 0.1617 mL 0.3233 mL 0.6467 mL 0.8083 mL
100 mM 0.0162 mL 0.0808 mL 0.1617 mL 0.3233 mL 0.4042 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on RGB-286638

RGB-286638 is a novel CDKs inhibitor that inhibits cyclin T1-CDK9, cyclin B1-CDK1, cyclin E-CDK2, cyclin D1-CDK4, cyclin E-CDK3 and p35-CDK5 with IC50 values of 1, 2, 3, 4, and 5 nM, respectively. RGB-286638 was less potent against cyclin D3-CDK6 and cyclin H-CDK7. Additionally, RGB-286638 also inhibits GSK-3β, TAK1, AMPK, Jak2 and MEK1 [1].

Cyclin-dependent kinases (CDKs) are a family of protein kinases regulating the cell cycle. CDKs are involved in regulating transcription, mRNA processing and the differentiation of nerve cells.

RGB-286638 is a novel indenopyrazole-derived CDK inhibitor. In MM cell lines with wild type (wt)-p53 or mutant p53, RGB-286638 resulted in MM cytotoxicity and induced caspase-dependent apoptosis that was closely associated with the downregulation of RNA polymerase II phosphorylation and inhibition of transcription. RGB-286638 induced p53 accumulation through loss of Mdm2 and nucleolar stress, accompanied by induction of p53 DNA binding activity [1].

In SCID mice xenografted MM.1S cells, RGB-286638 (30 mg/kg and 40 mg/kg) significantly inhibited MM tumor growth with maximum TGI (%) of 85.06% and 86.34%, respectively. RGB-286638 also improved survival with no toxic deaths [1]. In patients with solid tumors, RGB-286638 is tolerated at 120 mg/d for 5 days every 4 weeks. Also, RGB-286638 prolonged disease stabilization (2-14 months) [2].

References:
[1].  Cirstea D, Hideshima T, Santo L, et al. Small-molecule multi-targeted kinase inhibitor RGB-286638 triggers P53-dependent and -independent anti-multiple myeloma activity through inhibition of transcriptional CDKs. Leukemia, 2013, 27(12): 2366-2375.
[2].  van der Biessen DA, Burger H, de Bruijn P, et al. Phase I study of RGB-286638, a novel, multitargeted cyclin-dependent kinase inhibitor in patients with solid tumors. Clin Cancer Res, 2014, 20(18): 4776-4783.

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References on RGB-286638

Phase I study of RGB-286638, a novel, multitargeted cyclin-dependent kinase inhibitor in patients with solid tumors.[Pubmed:25024258]

Clin Cancer Res. 2014 Sep 15;20(18):4776-83.

PURPOSE: RGB-286638 is a multitargeted inhibitor with targets comprising the family of cyclin-dependent kinases (CDK) and a range of other cancer-relevant tyrosine and serine/threonine kinases. The objectives of this first in human trial of RGB-286638, given i.v. on days 1 to 5 every 28 days, were to determine the maximum tolerated dose (MTD) and to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of this new drug. EXPERIMENTAL DESIGN: Sequential cohorts of 3 to 6 patients were treated per dose level. Blood, urine samples, and skin biopsies for full PK and/or PD analyses were collected. RESULTS: Twenty-six patients were enrolled in 6-dose levels from 10 to 160 mg/d. Four dose-limiting toxicities were observed in 2 of the 6 patients enrolled at the highest dose level. These toxicities were AST/ALT elevations in 1 patient, paroxysmal supraventricular tachycardias (SVTs), hypotension, and an increase in troponin T in another patient. The plasma PK of RGB-286638 was shown to be linear over the studied doses. The interpatient variability in clearance was moderate (variation coefficient 7%-36%). The PD analyses in peripheral blood mononuclear cells, serum (apoptosis induction) and skin biopsies (Rb, p-Rb, Ki-67, and p27(KIP1) expression) did not demonstrate a consistent modulation of mechanism-related biomarkers with the exception of lowered Ki-67 levels at the MTD level. The recommended MTD for phase II studies is 120 mg/d. CONCLUSIONS: RGB-286638 is tolerated when administered at 120 mg/d for 5 days every 28 days. Prolonged disease stabilization (range, 2-14 months) was seen across different dose levels.

Validated bioanalytical method for the quantification of RGB-286638, a novel multi-targeted protein kinase inhibitor, in human plasma and urine by liquid chromatography/tandem triple-quadrupole mass spectrometry.[Pubmed:19628352]

J Pharm Biomed Anal. 2009 Dec 5;50(5):977-82.

A rapid and sensitive liquid chromatography/tandem mass spectrometry (LC-MS/MS) method has been developed and validated for the quantitative determination of RBG-286638, a novel multi-targeted protein kinase inhibitor, in 200 microl aliquots of human potassium EDTA plasma with deuterated RGB-286638 as internal standard. The sample extraction and cleaning-up involved a simple liquid-liquid extraction with 100 microl aliquots of acetonitrile and 1 ml aliquots of n-butylchloride. Urine was accurately 5- and 10-fold diluted in blank plasma prior to extraction. Chromatographic separations were achieved on a reversed phase C18 column eluted at a flow-rate of 0.250 ml/min on a gradient of 0.2 mM ammonium formate and acetonitrile both acidified with 0.1% formic acid. The overall cycle time of the method was 7 min, with RGB-286638 eluting at 1.9 min. The multiple reaction monitoring transitions were set at 546>402 (m/z), and 549>402 (m/z) for RGB-286638 and the internal standard, respectively. The calibration curves were linear over the range of 2.00 to 1000 ng/ml with the lower limit of quantitation validated at 2.00 ng/ml. The within-run and between-run precisions were within 7.90%, while the accuracy ranged from 92.2% to 99.7%. The method was successfully applied to samples derived from a clinical study.

Small-molecule multi-targeted kinase inhibitor RGB-286638 triggers P53-dependent and -independent anti-multiple myeloma activity through inhibition of transcriptional CDKs.[Pubmed:23807770]

Leukemia. 2013 Dec;27(12):2366-75.

Small-molecule multi-targeted cyclin-dependent kinase (CDK) inhibitors (CDKIs) are of particular interest due to their potent antitumor activity independent of p53 gene alterations. P53 deletion is associated with a very poor prognosis in multiple myeloma (MM). In this regard, we tested the anti-MM activity of RGB-286638, an indenopyrazole-derived CDKI with Ki-nanomolar activity against transcriptional CDKs. We examined RGB-286638's mode-of-action in MM cell lines with wild-type (wt)-p53 and those expressing mutant p53. RGB-286638 treatment resulted in MM cytotoxicity in vitro associated with inhibition of MM tumor growth and prolonged survival in vivo. RGB-286638 displayed caspase-dependent apoptosis in both wt-p53 and mutant-p53 cells that was closely associated with the downregulation of RNA polymerase II phosphorylation and inhibition of transcription. RGB-286638 triggered p53 accumulation via nucleolar stress and loss of Mdm2, accompanied by induction of p53 DNA-binding activity. In addition, RGB-286638 mediated p53-independent activity, which was confirmed by cytotoxicity in p53-knockdown and p53-mutant cells. We also demonstrated downregulation of oncogenic miR-19, miR-92a-1 and miR-21. Our data provide the rationale for the development of transcriptional CDKIs as therapeutic agents, which activate p53 in competent cells, while circumventing p53 deficiency through alternative p53-independent cell death mechanisms in p53-mutant/deleted cells.

Description

RGB-286638 is a CDK inhibitor that inhibits the kinase activity of cyclin T1-CDK9, cyclin B1-CDK1, cyclin E-CDK2, cyclin D1-CDK4, cyclin E-CDK3, and p35-CDK5 with IC50s of 1, 2, 3, 4, 5 and 5 nM, respectively; also inhibits GSK-3β, TAK1, Jak2 and MEK1, with IC50s of 3, 5, 50, and 54 nM.

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