RGB-286638 - CAS 784210-88-4
Catalog number: B0084-463330
Category: Inhibitor
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RGB-286638 is a novel CDK inhibitor. It inhibited several tyrosine and serine/threonine non-CDK enzymes, i.e. GSK-3β, TAK1, AMPK, Jak2, MEK1. It demonstrated equimolar (50nM) activity in freshly isolated tumor cells from MM patients, while manifesting less cytotoxicity in healthy donor PBMCs. It reduced the phosphorylation of Rb at S807/811 in MM.1S and MM.1R cells, but had no effects on p-Rb S780.
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B0084-463330 100 mg $299 In stock
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784210-87-3 (dihydrochloride)
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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; RGB 286638; RGB286638
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1.Targeting cell cycle regulators in hematologic malignancies.
Aleem E;Arceci RJ Front Cell Dev Biol. 2015 Apr 9;3:16. doi: 10.3389/fcell.2015.00016. eCollection 2015.
Hematologic malignancies represent the fourth most frequently diagnosed cancer in economically developed countries. In hematologic malignancies normal hematopoiesis is interrupted by uncontrolled growth of a genetically altered stem or progenitor cell (HSPC) that maintains its ability of self-renewal. Cyclin-dependent kinases (CDKs) not only regulate the mammalian cell cycle, but also influence other vital cellular processes, such as stem cell renewal, differentiation, transcription, epigenetic regulation, apoptosis, and DNA repair. Chromosomal translocations, amplification, overexpression and altered CDK activities have been described in different types of human cancer, which have made them attractive targets for pharmacological inhibition. Mouse models deficient for one or more CDKs have significantly contributed to our current understanding of the physiological functions of CDKs, as well as their roles in human cancer. The present review focuses on selected cell cycle kinases with recent emerging key functions in hematopoiesis and in hematopoietic malignancies, such as CDK6 and its role in MLL-rearranged leukemia and acute lymphocytic leukemia, CDK1 and its regulator WEE-1 in acute myeloid leukemia (AML), and cyclin C/CDK8/CDK19 complexes in T-cell acute lymphocytic leukemia.
2.Phase I study of RGB-286638, a novel, multitargeted cyclin-dependent kinase inhibitor in patients with solid tumors.
van der Biessen DA;Burger H;de Bruijn P;Lamers CH;Naus N;Loferer H;Wiemer EA;Mathijssen RH;de Jonge MJ Clin Cancer Res. 2014 Sep 15;20(18):4776-83. doi: 10.1158/1078-0432.CCR-14-0325. Epub 2014 Jul 14.
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.
3.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.
de Bruijn P;Moghaddam-Helmantel IM;de Jonge MJ;Meyer T;Lam MH;Verweij J;Wiemer EA;Loos WJ J Pharm Biomed Anal. 2009 Dec 5;50(5):977-82. doi: 10.1016/j.jpba.2009.06.048. Epub 2009 Jul 7.
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.
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CAS 784210-88-4 RGB-286638

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