Seliciclib

Seliciclib
Names
IUPAC name
2-(R)-(1-Ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine
Other names
Roscovitine; CYC202
Identifiers
186692-46-6 Yes
ChEMBL ChEMBL14762 
ChemSpider 140922 
Jmol-3D images Image
MeSH roscovitine
PubChem 160355
Properties
Molecular formula
 C19H26N6O
Molar mass 354.45 g·mol−1
Except where noted otherwise, data is given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
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Infobox references

Seliciclib (roscovitine or CYC202) is an experimental drug candidate 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), Cushing's Disease, leukemia, HIV infection, herpes simplex infection, cystic fibrosis[1] 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.[2] Seliciclib inhibits CDK2/E, CDK2/A, CDK7 and CDK9.[3]

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.[3][4] In the current APPRAISE trial, the research drug is undergoing Phase IIb clinical trial as a monotherapy for NSCLC in third-line patients.[5] 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".[4]

Seliciclib is also in clinical trials for B-cell lymphomas, including multiple myeloma. Seliciclib has been shown to inhibit RNA polymerase II-dependent transcription and down-regulation of the protein MCL1. [6][7]

Seliciclib is also a possible anti-viral agent. It causes the death of cells infected with HIV[8][9][10] and preventing the replication of Herpes simplex virus.[11][12]

Seliciclib has been shown in vitro to induce apoptosis in neutrophil granulocytes.[13] 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.

Seliciclib has been shown to cause parthogenetic egg activation. However it does create abnormal second polar bodies and therefore possible aneuploid zygotes. Egg activation usually involves calcium oscillations however this does not happen with Seliciclib. Seciclib causes egg activation by inhibiting protein kinases which results in the inactivation of the maturation promoting factor (MPF). [14]

References

  1. ↑ ,
  2. ↑ 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:10.1111/j.1432-1033.1997.0518a.x. PMID 9030780.
  3. ↑ 3.0 3.1 "Cyclacel Begins a Phase IIb Randomized Trial of Seliciclib for Previously Treated Non-Small Cell Lung Cancer". BIOWIRE. June 29, 2006.
  4. ↑ 4.0 4.1 "Cyclacel Reports Interim Seliciclib Phase IIa Data at 2005 ASCO". Business Wire. May 15, 2005.
  5. ↑ "Cyclacel Pharmaceuticals Reports Second Quarter 2006 Financial Results". Business Wire. August 14, 2006.
  6. ↑ 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:10.1158/0008-5472.CAN-05-0233. PMID 15958589.
  7. ↑ 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. doi:10.1182/blood-2005-01-0320. PMC 1895150. PMID 15827128.
  8. ↑ Sadaie MR, Mayner R, Doniger J (January 2004). "A novel approach to develop anti-HIV drugs: adapting non-nucleoside anticancer chemotherapeutics". Antiviral Research 61 (1): 1–18. doi:10.1016/j.antiviral.2003.09.004. PMID 14670589.
  9. ↑ 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:10.2174/138161206777442083. PMID 16787240.
  10. ↑ 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:10.1074/jbc.M406435200. PMID 15531588.
  11. ↑ 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:10.1128/JVI.74.5.2107-2120.2000. PMC 111691. PMID 10666240.
  12. ↑ 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:10.1128/JVI.78.17.9352-9365.2004. PMC 506918. PMID 15308730.
  13. ↑ 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:10.1038/nm1468. PMID 16951685.
  14. ↑ Doree M, Galas S. The cyclin-dependent protein kinases and the control of cell division. FASEB J 1994; 8:1114–1121