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Seliciclib

Description of Seliciclib: Seliciclib is an 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. CDKs, serine/threonine kinases that play an important role in cell cycle regulation, are overexpressed in various malignancies. Mcl-1 belongs to the Bcl-2 family of antiapoptotic proteins and is a protein crucial to the survival of a range of tumor cell types. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:    Cyclacel Pharmaceuticals, Inc.

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.).  

1: 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 10. doi: 10.1038/bjc.2011.566. [Epub ahead of print] PubMed PMID: 22233925.

2: 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.

3: 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. Epub 2010 Sep 6. PubMed PMID: 20822897.

4: 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. Epub 2010 Aug 10. PubMed PMID: 20699410.

5: 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. PubMed PMID: 20684776; PubMed Central PMCID: PMC3224749.

6: Aldoss IT, Tashi T, Ganti AK. Seliciclib in malignancies. Expert Opin Investig Drugs. 2009 Dec;18(12):1957-65. PubMed PMID: 19938906.

7: 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. PubMed PMID: 19911397.

8: 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. PubMed PMID: 19731111.

9: 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. Epub 2009 May 26. PubMed PMID: 19470731.

10: 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. PubMed PMID: 19228744.

11: 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. PubMed PMID: 19003963.

12: 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. PubMed PMID: 18594016.

13: 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. PubMed PMID: 18497689.

14: 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.

15: 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.

16: Hallaert DY, Spijker R, Jak M, Derks IA, Alves NL, Wensveen FM, de Boer JP, de Jong D, Green SR, van Oers MH, Eldering E. Crosstalk among Bcl-2 family members in B-CLL: seliciclib acts via the Mcl-1/Noxa axis and gradual exhaustion of Bcl-2 protection. Cell Death Differ. 2007 Nov;14(11):1958-67. Epub 2007 Aug 17. PubMed PMID: 17703234.

17: Biglione S, Byers SA, Price JP, Nguyen VT, Bensaude O, Price DH, Maury W. Inhibition of HIV-1 replication by P-TEFb inhibitors DRB, seliciclib and flavopiridol correlates with release of free P-TEFb from the large, inactive form of the complex. Retrovirology. 2007 Jul 11;4:47. PubMed PMID: 17625008; PubMed Central PMCID: PMC1948018.

18: Coley HM, Shotton CF, Thomas H. Seliciclib (CYC202; r-roscovitine) in combination with cytotoxic agents in human uterine sarcoma cell lines. Anticancer Res. 2007 Jan-Feb;27(1A):273-8. PubMed PMID: 17352243.

19: Lacrima K, Rinaldi A, Vignati S, Martin V, Tibiletti MG, Gaidano G, Catapano CV, Bertoni F. Cyclin-dependent kinase inhibitor seliciclib shows in vitro activity in diffuse large B-cell lymphomas. Leuk Lymphoma. 2007 Jan;48(1):158-67. PubMed PMID: 17325859.

20: Coley HM, Shotton CF, Kokkinos MI, Thomas H. The effects of the CDK inhibitor seliciclib alone or in combination with cisplatin in human uterine sarcoma cell lines. Gynecol Oncol. 2007 May;105(2):462-9. Epub 2007 Feb 14. PubMed PMID: 17300833.

21: Benson C, White J, De Bono J, O'Donnell A, Raynaud F, Cruickshank C, McGrath H, Walton M, Workman P, Kaye S, Cassidy J, Gianella-Borradori A, Judson I, Twelves C. A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-Roscovitine), administered twice daily for 7 days every 21 days. Br J Cancer. 2007 Jan 15;96(1):29-37. Epub 2006 Dec 19. PubMed PMID: 17179992; PubMed Central PMCID: PMC2360206.

22: Iurisci I, Filipski E, Reinhardt J, Bach S, Gianella-Borradori A, Iacobelli S, Meijer L, Lévi F. Improved tumor control through circadian clock induction by Seliciclib, a cyclin-dependent kinase inhibitor. Cancer Res. 2006 Nov 15;66(22):10720-8. PubMed PMID: 17108108.

23: Ribas J, Boix J, Meijer L. (R)-roscovitine (CYC202, Seliciclib) sensitizes SH-SY5Y neuroblastoma cells to nutlin-3-induced apoptosis. Exp Cell Res. 2006 Jul 15;312(12):2394-400. PubMed PMID: 16765943.

24: MacCallum DE, Melville J, Frame S, Watt K, Anderson S, Gianella-Borradori A, Lane DP, Green SR. Seliciclib (CYC202, R-Roscovitine) induces cell death in multiple myeloma cells by inhibition of RNA polymerase II-dependent transcription and down-regulation of Mcl-1. Cancer Res. 2005 Jun 15;65(12):5399-407. PubMed PMID: 15958589.

25: Lacrima K, Valentini A, Lambertini C, Taborelli M, Rinaldi A, Zucca E, Catapano C, Cavalli F, Gianella-Borradori A, Maccallum DE, Bertoni F. In vitro activity of cyclin-dependent kinase inhibitor CYC202 (Seliciclib, R-roscovitine) in mantle cell lymphomas. Ann Oncol. 2005 Jul;16(7):1169-76. Epub 2005 Apr 25. PubMed PMID: 15851403.

26: Raje N, Kumar S, Hideshima T, Roccaro A, Ishitsuka K, Yasui H, Shiraishi N, Chauhan D, Munshi NC, Green SR, Anderson KC. Seliciclib (CYC202 or R-roscovitine), a small-molecule cyclin-dependent kinase inhibitor, mediates activity via down-regulation of Mcl-1 in multiple myeloma. Blood. 2005 Aug 1;106(3):1042-7. Epub 2005 Apr 12. PubMed PMID: 15827128; PubMed Central PMCID: PMC1895150.