WHAT IS ROSCOVITINE?
(R)-Roscovitine is often referred to as a selective inhibitor of cyclin-dependent kinases. Besides its use as a biological tool in cell cycle, neuronal functions, and apoptosis studies, it is currently evaluated as a potential drug to treat cancers, neurodegenerative diseases, viral infections, and glomerulonephritis.
(R)-Roscovitine is rather selective for CDKs, in fact most kinases are not affected. However, it binds an unexpected, non-protein kinase target, pyridoxal kinase, the enzyme responsible for phosphorylation and activation of vitamin B6. These results could help in interpreting the cellular actions of Roscovitine but also in guiding the synthesis of more selective roscovitine analogs.
(R)-Roscovitine is a 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. Roscovitineis being developed by Cyclacel.
(R)-Roscovitine is being researched for the treatment of non-small cell lung cancer (NSCLC), leukemia, HIV infection, herpes simplex infection, cystic fibrosis and the mechanisms of chronic inflammation disorders.
Roscovitine is a 2,6,9-substituted purine analog. Its structure in complex with CDK2 was determined in 1996. (R)-Roscovitine inhibits CDK2/E, CDK2/A, CDK7 and CDK9.
(R)-Roscovitine 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. In the current APPRAISE trial, the research drug is undergoing Phase IIb clinical trial as a monotherapy for NSCLC in third-line patients 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".
Roscovitine is also in clinical trials for B-cell lymphomas, including acute myelogenous leukemia. Roscovitine has been shown to inhibit RNA polymerase II-dependent transcription and down-regulation of myeloid cell leukaemia sequence 1 (Mcl-1).
Roscovitine is also a possible anti-viral agent. It causes the death of cells infected with HIV and preventing the replication of Herpes simplex virus.
Sources: De Azevedo WF, Leclerc S, Meijer L, Havlicek L, Strnad M, Kim SH