RGB-286638 - CAS 784210-87-3
Catalog number: 784210-87-3
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.
RGB-286638; RGB286638; RGB286638
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1.Phase I study of RGB-286638, a novel, multitargeted cyclin-dependent kinase inhibitor in patients with solid tumors.
van der Biessen DA1, Burger H1, de Bruijn P1, Lamers CH1, Naus N2, Loferer H3, Wiemer EA1, Mathijssen RH1, de Jonge MJ4. 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.
2.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 P1, 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.
3.Small-molecule multi-targeted kinase inhibitor RGB-286638 triggers P53-dependent and -independent anti-multiple myeloma activity through inhibition of transcriptional CDKs.
Cirstea D1, Hideshima T, Santo L, Eda H, Mishima Y, Nemani N, Hu Y, Mimura N, Cottini F, Gorgun G, Ohguchi H, Suzuki R, Loferer H, Munshi NC, Anderson KC, Raje N. Leukemia. 2013 Dec;27(12):2366-75. doi: 10.1038/leu.2013.194. Epub 2013 Jun 28.
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.
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CAS 784210-87-3 RGB-286638

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