Seliciclib

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IUPACName = 2-(R)-(1-Ethyl-2-hydroxyethylamino)-
6-benzylamino-9-isopropylpurine
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CASNo = 186692-46-6
PubChem = 160355
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MeSHName = roscovitine
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Formula = C₁₉H₂₆N₆O
MolarMass = 354.5 g/mol
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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.cite journal | author= De Azevedo WF, Leclerc S, Meijer L, Havlicek L, Strnad M, Kim SH | title=Inhibition of cyclin-dependent kinases by purine analogues: crystal structure of human cdk2 complexed with roscovitine | journal=Eur J Biochem | volume=243 | issue=1-2 | year=1997 | pages=518–526 | pmid=9030780 | doi=10.1111/j.1432-1033.1997.0518a.x ] Seliciclib inhibits CDK2/E, CDK2/A, CDK7 and CDK9.cite web|url=http://www.genengnews.com/news/bnitem.aspx?name=3002660|title=Cyclacel Begins a Phase IIb Randomized Trial of Seliciclib for Previously Treated Non-Small Cell Lung Cancer|publisher=BIOWIRE|date=June 29, 2006]

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.cite web|url=http://www.findarticles.com/p/articles/mi_m0EIN/is_2005_May_15/ai_n13718674|title=Cyclacel Reports Interim Seliciclib Phase IIa Data at 2005 ASCO|publisher=Business Wire|date=May 15, 2005] In the current "APPRAISE" trial, the research drug is undergoing Phase IIb clinical trial as a monotherapy for NSCLC in third-line patients. [cite web|url=http://www.nasdaq.com//aspxcontent/newsstory.aspx?selected=CYCC&symbol=CYCC&textpath=20060814%5CACQBIZ200608141711BIZWIRE%5FUSPR%5F%5F%5F%5F%5FBW6007%2Ehtm&cdtime=08%2F14%2F2006+5%3A11PM|title=Cyclacel Pharmaceuticals Reports Second Quarter 2006 Financial Results|publisher=Business Wire|date=August 14, 2006] 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".

Seliciclib is also in clinical trials for B-cell lymphomas, including acute myelogenous leukemia.Fact|date=June 2008 Seliciclib has been shown to inhibit RNA polymerase II-dependent transcription and down-regulation of myeloid cell leukaemia sequence 1 (Mcl-1). [cite journal | author=MacCallum DE, Melville J, Frame S, Watt K, Anderson S, Gianella-Borradori A, Lane DP, Green SR | title=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 | journal=Cancer Research | volume=65 | issue=12 | year=2005| pages=5399–5407 | pmid=15958589 | doi=10.1158/0008-5472.CAN-05-0233 ] [cite journal|author=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|title=Seliciclib (CYC202 or R-roscovitine), a small-molecule cyclin-dependent kinase inhibitor, mediates activity via down-regulation of Mcl-1 in multiple myeloma|journal=Blood | volume=106|issue=3|date=August 1, 2005|pages=1042–1047|pmid=15827128]

Seliciclib is also a possible anti-viral agent. It causes the death of cells infected with HIV [cite journal|title=A novel approach to develop anti-HIV drugs: adapting non-nucleoside anticancer chemotherapeutics|author=Sadaie MR, Mayner R, Doniger J|date=2004 Jan|volume=61|issue=1|pages=1–18|pmid=14670589] [cite journal|title=Potential use of pharmacological cyclin-dependent kinase inhibitors as anti-HIV therapeutics|author=Pumfery A, de la Fuente C, Berro R, Nekhai S, Kashanchi F, Chao SH|year=2006|volume=12|issue=16|pages=1949–61|journal=Curr Pharm Des.|doi=10.2174/138161206777442083] [cite journal|author=Agbottah E, de La Fuente C, Nekhai S, Barnett A, Gianella-Borradori A, Pumfery A, Kashanchi F|title=Antiviral activity of CYC202 in HIV-1-infected cells|journal=J. Biol. Chem.|date=28 Jan 2005|volume=280|issue=4|pages=3029–42|pmid=15531588|doi=10.1074/jbc.M406435200] and preventing the replication of Herpes simplex virus. [cite journal | author = Schang LM, Rosenberg A, Schaffer PA | title = Roscovitine, a specific inhibitor of cellular cyclin-dependent kinases, inhibits herpes simplex virus DNA synthesis in the presence of viral early proteins | journal = J Virol. | year = 2000 | volume = 74 | issue = 5 | pages = 2107–20 | pmid=10666240 | doi = 10.1128/JVI.74.5.2107-2120.2000] cite journal | author=Diwan P, Lacasse JJ, Schang LM. | title=Roscovitine inhibits activation of promoters in herpes simplex virus type 1 genomes independently of promoter-specific factors | journal=J. Virol. | year=2004 | pages=9352–9365 | volume=78 | issue=17 | pmid=15308730 | doi=10.1128/JVI.78.17.9352-9365.2004]

Seliciclib has been shown "in vitro" to induce apoptosis in neutrophil granulocytes. [cite journal | author=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 | title=Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis | journal=Nature Medicine | volume=12 | issue=9 | year=2006| pages=1056–1064 | pmid=16951685 | doi=10.1038/nm1468] 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