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| Seliciclib | |
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| IUPAC name | 2-(R)-(1-Ethyl-2-hydroxyethylamino)- 6-benzylamino-9-isopropylpurine |
| Identifiers | |
| CAS number | 186692-46-6 |
| PubChem | |
| MeSH | |
| Properties | |
| Molecular formula | C19H26N6O |
| Molar mass | 354.5 g/mol |
| Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) Infobox references |
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R-roscovitine (Seliciclib or CYC202) is a trial drug in the family of pharmacological cyclin-dependent kinase (CDK) inhibitors that preferentially inhibit multiple enzyme targets including CDK2, CDK7 and CDK9, which alter the growth phase or state within the cell cycle of treated cells. Seliciclib is being developed by Cyclacel.
Seliciclib is being researched for the treatment of non-small cell lung cancer (NSCLC), leukemia, HIV infection, herpes simplex infection, and the mechanisms of chronic inflammation disorders.
Seliciclib is a 2,6,9-substituted purine analog. Its structure in complex with CDK2 was determined in 1996.1 Seliciclib inhibits CDK2/E, CDK2/A, CDK7 and CDK9.2
Uses
Seliciclib has been found to produce apoptosis in treated cancerous cells of non-small cell lung cancer (NSCLC) and other cancers. Seliciclib has previously undergone Phase IIa clinical trials, in 240 NSCLC patients as a combined dose with existing first- and second-line treatments.23 In the current APPRAISE trial, the research drug is undergoing Phase IIb clinical trial as a monotherapy for NSCLC in third-line patients.4 The side-effects reported in Phase I trials of Seliciclib for NSCLC were "nausea, vomiting, transient elevations in serum creatinine and liver function parameters and transient hypokalemia".3
Seliciclib is also in clinical trials for B-cell lymphomas, including acute myelogenous leukemia.citation needed Seliciclib has been shown to inhibit RNA polymerase II-dependent transcription and down-regulation of myeloid cell leukaemia sequence 1 (Mcl-1). 56
Seliciclib is also a possible anti-viral agent. It causes the death of cells infected with HIV789 and preventing the replication of Herpes simplex virus.1011
Seliciclib has been shown in vitro to induce apoptosis in neutrophil granulocytes.12 If this mechanism turns out to be safe, reliable and efficient in vivo, the drug could improve treatment of chronic inflammation diseases such as cystic fibrosis and arthritis. These are usually treated with glucocorticoids which often have serious side effects.
References
- ^ De Azevedo WF, Leclerc S, Meijer L, Havlicek L, Strnad M, Kim SH (1997). "Inhibition of cyclin-dependent kinases by purine analogues: crystal structure of human cdk2 complexed with roscovitine". Eur J Biochem 243 (1-2): 518–526. doi:. PMID 9030780.
- ^ a b "Cyclacel Begins a Phase IIb Randomized Trial of Seliciclib for Previously Treated Non-Small Cell Lung Cancer". BIOWIRE (June 29, 2006).
- ^ a b "Cyclacel Reports Interim Seliciclib Phase IIa Data at 2005 ASCO". Business Wire (May 15, 2005).
- ^ "Cyclacel Pharmaceuticals Reports Second Quarter 2006 Financial Results". Business Wire (August 14, 2006).
- ^ MacCallum DE, Melville J, Frame S, Watt K, Anderson S, Gianella-Borradori A, Lane DP, Green SR (2005). "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 Research 65 (12): 5399–5407. doi:. PMID 15958589.
- ^ Noopur Raje, Shaji Kumar, Teru Hideshima, Aldo Roccaro, Kenji Ishitsuka, Hiroshi Yasui, Norihiko Shiraishi, Dharminder Chauhan, Nikhil C. Munshi, Simon R. Green, and Kenneth C. Anderson (August 1, 2005). "Seliciclib (CYC202 or R-roscovitine), a small-molecule cyclin-dependent kinase inhibitor, mediates activity via down-regulation of Mcl-1 in multiple myeloma". Blood 106 (3): 1042–1047. PMID 15827128.
- ^ Sadaie MR, Mayner R, Doniger J (January 2004). A novel approach to develop anti-HIV drugs: adapting non-nucleoside anticancer chemotherapeutics. 61. pp. 1–18. PMID 14670589.
- ^ Pumfery A, de la Fuente C, Berro R, Nekhai S, Kashanchi F, Chao SH (2006). "Potential use of pharmacological cyclin-dependent kinase inhibitors as anti-HIV therapeutics". Curr Pharm Des. 12 (16): 1949–61. doi:.
- ^ Agbottah E, de La Fuente C, Nekhai S, Barnett A, Gianella-Borradori A, Pumfery A, Kashanchi F (28 January 2005). "Antiviral activity of CYC202 in HIV-1-infected cells". J. Biol. Chem. 280 (4): 3029–42. doi:. PMID 15531588.
- ^ Schang LM, Rosenberg A, Schaffer PA (2000). "Roscovitine, a specific inhibitor of cellular cyclin-dependent kinases, inhibits herpes simplex virus DNA synthesis in the presence of viral early proteins". J Virol. 74 (5): 2107–20. doi:. PMID 10666240.
- ^ Diwan P, Lacasse JJ, Schang LM. (2004). "Roscovitine inhibits activation of promoters in herpes simplex virus type 1 genomes independently of promoter-specific factors". J. Virol. 78 (17): 9352–9365. doi:. PMID 15308730.
- ^ Rossi AG, Sawatzky DA, Walker A, Ward C, Sheldrake TA, Riley NA, Caldicott A, Martinez-Losa M, Walker TR, Duffin R, Gray M, Crescenzi E, Martin MC, Brady HJ, Savill JS, Dransfield I, Haslett C (2006). "Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis". Nature Medicine 12 (9): 1056–1064. doi:. PMID 16951685.
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