Seliciclib (roscovitine orCYC202) is an experimental drug candidate in the family of pharmacologicalcyclin-dependent kinase (CDK) inhibitors that inhibit multiple enzyme targets includingCDK2,CDK7 andCDK9, which alter the growth phase or state within thecell cycle of treatedcells. Seliciclib is being developed byCyclacel.
This[which?] is a phase II, dose ranging, multicenter, randomized, double-blind, placebo-controlled study. The aim of this study is to assess the safety of increasing doses of roscovitine administered orally for 4 cycles of 4 consecutive days separated by a 3 days treatment free period in adult CF subjects withcystic fibrosis carrying two cystic fibrosis-causing mutations with at least one F508del-CFTR mutation and chronically infected withPseudomonas aeruginosa. This study involved 36 cystic fibrosis patients including 24 treated and 12 controls.[1]
Seliciclib is a 2,6,9-substitutedpurine analog. Its structure in complex with CDK2 was determined in 1996.[3] Seliciclib inhibits CDK2/E, CDK2/A, CDK7 and CDK9.[4]
Seliciclib has been found to produceapoptosis in treated cancerous cells of non-small cell lung cancer (NSCLC) and other cancers. Seliciclib has previously undergonePhase IIa clinical trials, in 240 NSCLC patients as a combined dose with existing first- and second-line treatments.[4][5] In the currentAPPRAISE trial, the research drug is undergoing Phase IIb clinical trial as a monotherapy for NSCLC in third-line patients.[6] Theside-effects reported in Phase I trials of seliciclib for NSCLC were "nausea, vomiting, transient elevations in serum creatinine and liver function parameters and transienthypokalemia".[5]
Seliciclib has been shownin vitro to induceapoptosis inneutrophil granulocytes.[9] If this mechanism turns out to be safe, reliable and efficientin vivo, the drug could improve treatment of chronic inflammation diseases such ascystic fibrosis andarthritis. These are usually treated withglucocorticoids which often have serious side effects
Seliciclib has been shown to cause parthenogenetic 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).[19]
Causes severe side effects that can not be tolerated on daily dosing. Side effects includehypokalemia and elevation of liver enzymes.[21] Due to these side effects, seliciclib has not been approved by the USFDA.
^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.PMID15958589.
^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.PMID16951685.S2CID5875865.
^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.PMID16787240.
^Yu, Alan S. L., Chertow, Glenn M., Luyckx, Valérie A., Marsden, Philip A., Skorecki, Karl, Taal, Maarten W., eds. (25 September 2019).Brenner & Rector's the kidney. Elsevier Health Sciences.ISBN978-0-323-55085-7.OCLC1122857051.
^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 (December 2010). "Phase I evaluation of seliciclib (R-roscovitine), a novel oral cyclin-dependent kinase inhibitor, in patients with advanced malignancies".European Journal of Cancer.46 (18):3243–3250.doi:10.1016/j.ejca.2010.08.001.ISSN1879-0852.PMID20822897.
