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.

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.

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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