WARNING: This product is for research use only, not for human or veterinary use.
Hodoodo CAT#: H202580
CAS#: 186692-46-6
Description: Seliciclib, also known as roscovitine and CYC202, is a n orally bioavailable, small-molecule cyclin-dependent kinase (CDK) inhibitor with potential proapoptotic and antineoplastic activities. Seliciclib primarily inhibits CDK2/E, CDK2/A, CDK7 and CDK9 by competing for their ATP binding sites, leading to a disruption of cell cycle progression. In addition, this agent appears to interfere with CDK-mediated phosphorylation of the carboxy-terminal domain of RNA polymerase II, inhibiting RNA polymerase II-dependent transcription, which may result in the down-regulation of antiapoptotic proteins such as induced myeloid leukemia cell differentiation protein Mcl-1.
Hodoodo Cat#: H202580
Name: Seliciclib (Roscovitine)
CAS#: 186692-46-6
Chemical Formula: C19H26N6O
Exact Mass: 354.22
Molecular Weight: 354.440
Elemental Analysis: C, 64.38; H, 7.39; N, 23.71; O, 4.51
Synonym: CYC202; CYC202; CYC 202; R-Roscovitine; Roscovitin; Roscovitine; Seliciclib.
IUPAC/Chemical Name: (R)-2-((6-(benzylamino)-9-isopropyl-9H-purin-2-yl)amino)butan-1-ol
InChi Key: BTIHMVBBUGXLCJ-OAHLLOKOSA-N
InChi Code: InChI=1S/C19H26N6O/c1-4-15(11-26)22-19-23-17(20-10-14-8-6-5-7-9-14)16-18(24-19)25(12-21-16)13(2)3/h5-9,12-13,15,26H,4,10-11H2,1-3H3,(H2,20,22,23,24)/t15-/m1/s1
SMILES Code: CC[C@@H](NC1=NC(NCC2=CC=CC=C2)=C3N=CN(C(C)C)C3=N1)CO
Appearance: Solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
More Info: Phase I trial of Selicilib: Fifty-six patients received a total of 218 cycles of seliciclib. Dose-Limiting Toxicities (DLT) consisting of nausea, vomiting, asthenia and hypokalaemia occurred at 1600 mg bid for schedule A and in schedule C, DLT of hypokalaemia and asthenia occurred at 1800 mg bid. The evaluation of longer treatment duration in schedule B was discontinued because of unacceptable toxicity at lower doses. Other adverse events included transient serum creatinine increases and liver dysfunctions. Pharmacokinetic data showed that exposure to seliciclib and its carboxylate metabolite increased with increasing dose. Soluble cytokeratin 18 fragments allowed monitoring of seliciclib-induced cell death in the blood of patients treated with seliciclib at doses above 800 mg/d. One partial response in a patient with hepatocellular carcinoma and sustained tumour stabilisations were observed. The MTD and RD for seliciclib are 1250 mg bid for 5d every 3 weeks and 1600 mg bid for 3d every 2 weeks, respectively. ( Eur J Cancer. 2010 Dec;46(18):3243-50. ).
| Biological target: | Seliciclib (Roscovitine) is an orally bioavailable and selective CDKs inhibitor with IC50s of 0.2 μM, 0.65 μM, and 0.7 μM for CDK5, Cdc2, and CDK2, respectively. |
| In vitro activity: | To further explore whether CDK5 inhibition inactivates ERK1/2/PPARγ and the EMT process, roscovitine was used to treat high glucose cultured NRK52E cells. Downstream gene expressions and biological features were investigated. Immunofluorescence microscopy revealed that roscovitine decreased phosphorylated ERK1/2 and PPARγ (Figure 6A). Correspondingly, roscovitine decreased the level of CDK5 and p35 with upregulation of E-cadherin, but downregulation of Vimentin and Collagen IV (Figure 6B and 6C). Moreover, roscovitine inhibited the ability of high glucose cultured NRK52E cells to migrate (Figure 6D) and invade (Figure 6E). Reference: Oncotarget. 2016 Jun 14;7(24):36510-36528. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/27145370/ |
| In vivo activity: | To test the potential of roscovitine as a selective agent against HPV+ head and neck cancers, a NUDE mouse-based xenograft assay was utilized. Mice were injected with HPV-positive UMSCC47 cells, and after tumors reached a measurable size, the mice were given 16.5 mg/kg doses of intraperitoneal roscovitine or vehicle injections. Tumor sizes were measured two times per week and mice were sacrificed when tumor volumes reached or exceeded 0.5 cm3. Roscovitine significantly reduced the rate of tumor growth (Figure 7A) and increased survival (Figure 7B) of treated mice. Strikingly, roscovitine treatment led to complete tumor disappearance in one mouse (25%); moreover, no tumor regrowth in this mouse was found 5 months after completion of the treatment (Figure 7B). Mouse weights did not differ significantly between mice treated with roscovitine and control mice, and behavioral differences between the two groups were also negligible. These results suggest that roscovitine can be used effectively as a selective tumor growth inhibitor in HPV+ head and neck cancer. Reference: Oncotarget. 2016 Jun 21;7(25):38598-38611. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/27233076/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 71.0 | 200.31 | |
| Ethanol | 71.0 | 200.31 |
The following data is based on the product molecular weight 354.44 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
| Formulation protocol: | |
| In vitro protocol: | 1. Bai X, Hou X, Tian J, Geng J, Li X. CDK5 promotes renal tubulointerstitial fibrosis in diabetic nephropathy via ERK1/2/PPARγ pathway. Oncotarget. 2016 Jun 14;7(24):36510-36528. doi: 10.18632/oncotarget.9058. PMID: 27145370; PMCID: PMC5095017. 2. Gary C, Hajek M, Biktasova A, Bellinger G, Yarbrough WG, Issaeva N. Selective antitumor activity of roscovitine in head and neck cancer. Oncotarget. 2016 Jun 21;7(25):38598-38611. doi: 10.18632/oncotarget.9560. PMID: 27233076; PMCID: PMC5122414. |
| In vivo protocol: | 1. Gary C, Hajek M, Biktasova A, Bellinger G, Yarbrough WG, Issaeva N. Selective antitumor activity of roscovitine in head and neck cancer. Oncotarget. 2016 Jun 21;7(25):38598-38611. doi: 10.18632/oncotarget.9560. PMID: 27233076; PMCID: PMC5122414. |
1: Khalil HS, Mitev V, Vlaykova T, Cavicchi L, Zhelev N. Discovery and development of Seliciclib. How systems biology approaches can lead to better drug performance. J Biotechnol. 2015 Mar 6. pii: S0168-1656(15)00094-2. doi: 10.1016/j.jbiotec.2015.02.032. [Epub ahead of print] PubMed PMID: 25747275.
2: Jackson RC, Radivoyevitch T. Modelling c-Abl Signalling in Activated Neutrophils: the Anti-inflammatory Effect of Seliciclib. Biodiscovery. 2013 Mar 1;7(4):4. PubMed PMID: 24765523; PubMed Central PMCID: PMC3994723.
3: Nutter F, Khwaja A, Haylor J. Seliciclib inhibits renal hypertrophy but not fibrosis in the rat following subtotal nephrectomy. Nephron Exp Nephrol. 2012;122(3-4):114-22. doi: 10.1159/000350248. Epub 2013 May 8. PubMed PMID: 23689642.
4: Josefsberg Ben-Yehoshua L, Beider K, Shimoni A, Ostrovsky O, Samookh M, Peled A, Nagler A. Characterization of cyclin E expression in multiple myeloma and its functional role in seliciclib-induced apoptotic cell death. PLoS One. 2012;7(4):e33856. doi: 10.1371/journal.pone.0033856. Epub 2012 Apr 25. PubMed PMID: 22558078; PubMed Central PMCID: PMC3338814.
5: Coley HM, Safuwan NA, Chivers P, Papacharalbous E, Giannopoulos T, Butler-Manuel S, Madhuri K, Lovell DP, Crook T. The cyclin-dependent kinase inhibitor p57(Kip2) is epigenetically regulated in carboplatin resistance and results in collateral sensitivity to the CDK inhibitor seliciclib in ovarian cancer. Br J Cancer. 2012 Jan 31;106(3):482-9. doi: 10.1038/bjc.2011.566. Epub 2012 Jan 10. PubMed PMID: 22233925; PubMed Central PMCID: PMC3273354.
6: Sheryanna AM, Smith J, Bhangal G, Barnett A, McClue S, Tam FW, Cook T, Pusey CD. Treatment with a cyclin-dependent kinase inhibitor, seliciclib, is effective in reducing glomerular macrophage numbers and the severity of established experimental glomerulonephritis. Nephrology (Carlton). 2011 May;16(4):410-6. doi: 10.1111/j.1440-1797.2010.01416.x. PubMed PMID: 21518118.
7: Le Tourneau C, Faivre S, Laurence V, Delbaldo C, Vera K, Girre V, Chiao J, Armour S, Frame S, Green SR, Gianella-Borradori A, Diéras V, Raymond E. Phase I evaluation of seliciclib (R-roscovitine), a novel oral cyclin-dependent kinase inhibitor, in patients with advanced malignancies. Eur J Cancer. 2010 Dec;46(18):3243-50. doi: 10.1016/j.ejca.2010.08.001. Epub 2010 Sep 6. PubMed PMID: 20822897.
8: Rajnai Z, Méhn D, Beéry E, Okyar A, Jani M, Tóth GK, Fülöp F, Lévi F, Krajcsi P. ATP-binding cassette B1 transports seliciclib (R-roscovitine), a cyclin-dependent kinase inhibitor. Drug Metab Dispos. 2010 Nov;38(11):2000-6. doi: 10.1124/dmd.110.032805. Epub 2010 Aug 10. PubMed PMID: 20699410.
9: Federico M, Symonds CE, Bagella L, Rizzolio F, Fanale D, Russo A, Giordano A. R-Roscovitine (Seliciclib) prevents DNA damage-induced cyclin A1 upregulation and hinders non-homologous end-joining (NHEJ) DNA repair. Mol Cancer. 2010 Aug 4;9:208. doi: 10.1186/1476-4598-9-208. PubMed PMID: 20684776; PubMed Central PMCID: PMC3224749.
10: Aldoss IT, Tashi T, Ganti AK. Seliciclib in malignancies. Expert Opin Investig Drugs. 2009 Dec;18(12):1957-65. doi: 10.1517/13543780903418445. PubMed PMID: 19938906.
11: Rogalińska M, Błoński JZ, Komina O, Góralski P, Zołnierczyk JD, Piekarski H, Robak T, Kiliańska ZM, Wesierska-Gadek J. R-roscovitine (Seliciclib) affects CLL cells more strongly than combinations of fludarabine or cladribine with cyclophosphamide: Inhibition of CDK7 sensitizes leukemic cells to caspase-dependent apoptosis. J Cell Biochem. 2010 Jan 1;109(1):217-35. doi: 10.1002/jcb.22400. PubMed PMID: 19911397.
12: Iurisci I, Filipski E, Sallam H, Harper F, Guettier C, Maire I, Hassan M, Iacobelli S, Lévi F. Liver circadian clock, a pharmacologic target of cyclin-dependent kinase inhibitor seliciclib. Chronobiol Int. 2009 Aug;26(6):1169-88. doi: 10.3109/07420520903209942. PubMed PMID: 19731111.
13: Hui AB, Yue S, Shi W, Alajez NM, Ito E, Green SR, Frame S, O'Sullivan B, Liu FF. Therapeutic efficacy of seliciclib in combination with ionizing radiation for human nasopharyngeal carcinoma. Clin Cancer Res. 2009 Jun 1;15(11):3716-24. doi: 10.1158/1078-0432.CCR-08-2790. Epub 2009 May 26. PubMed PMID: 19470731.
14: Hsieh WS, Soo R, Peh BK, Loh T, Dong D, Soh D, Wong LS, Green S, Chiao J, Cui CY, Lai YF, Lee SC, Mow B, Soong R, Salto-Tellez M, Goh BC. Pharmacodynamic effects of seliciclib, an orally administered cell cycle modulator, in undifferentiated nasopharyngeal cancer. Clin Cancer Res. 2009 Feb 15;15(4):1435-42. doi: 10.1158/1078-0432.CCR-08-1748. PubMed PMID: 19228744.
15: Appleyard MV, O'Neill MA, Murray KE, Paulin FE, Bray SE, Kernohan NM, Levison DA, Lane DP, Thompson AM. Seliciclib (CYC202, R-roscovitine) enhances the antitumor effect of doxorubicin in vivo in a breast cancer xenograft model. Int J Cancer. 2009 Jan 15;124(2):465-72. doi: 10.1002/ijc.23938. PubMed PMID: 19003963.
16: Fleming IN, Hogben M, Frame S, McClue SJ, Green SR. Synergistic inhibition of ErbB signaling by combined treatment with seliciclib and ErbB-targeting agents. Clin Cancer Res. 2008 Jul 1;14(13):4326-35. doi: 10.1158/1078-0432.CCR-07-4633. PubMed PMID: 18594016.
17: Pezzotta A, Mister M, Monteferrante G, Cassis L, Azzollini N, Aiello S, Satta M, Benigni A, Remuzzi G, Noris M. Effect of seliciclib (CYC202, R-roscovitine) on lymphocyte alloreactivity and acute kidney allograft rejection in rat. Transplantation. 2008 May 27;85(10):1476-82. doi: 10.1097/TP.0b013e31816f240c. PubMed PMID: 18497689.
18: Jackson RC, Barnett AL, McClue SJ, Green SR. Seliciclib, a cell-cycle modulator that acts through the inhibition of cyclin-dependent kinases. Expert Opin Drug Discov. 2008 Jan;3(1):131-43. doi: 10.1517/17460441.3.1.131. PubMed PMID: 23480144.
19: Whittaker SR, Te Poele RH, Chan F, Linardopoulos S, Walton MI, Garrett MD, Workman P. The cyclin-dependent kinase inhibitor seliciclib (R-roscovitine; CYC202) decreases the expression of mitotic control genes and prevents entry into mitosis. Cell Cycle. 2007 Dec 15;6(24):3114-31. Epub 2007 Oct 5. PubMed PMID: 18075315.
20: McClue SJ, Stuart I. Metabolism of the trisubstituted purine cyclin-dependent kinase inhibitor seliciclib (R-roscovitine) in vitro and in vivo. Drug Metab Dispos. 2008 Mar;36(3):561-70. Epub 2007 Nov 29. PubMed PMID: 18048486.
