MedKoo product information:

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.