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.This 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 (treatment "on") separated by a 3 days treatment free period (treatment "off") in adult CF subjects with Cystic Fibrosis carrying 2 Cystic Fibrosis causing mutations with at least one F508del-CFTR mutation and chronically infected with Pseudomonas aeruginosa.
This study involved 36 Cystic Fibrosis patients: 24 treated and 12 controls.[1]
Seliciclib is a 2,6,9-substituted
purine analog. Its structure in complex with CDK2 was determined in 1996.[3] Seliciclib inhibits CDK2/E, CDK2/A, CDK7 and CDK9.[4]
Clinical trials and lab tests
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Cancer treatment
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.[4][5] In the current APPRAISE trial, the research drug is undergoing Phase IIb clinical trial as a monotherapy for NSCLC in third-line patients.[6] 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".[5]
Seliciclib has been shown in vitro to induce
apoptosis in
neutrophil granulocytes.[9] 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 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]
Renal hypertrophy
Seliciclib reduces renal hypertrophy by 45% after 5/6 nephrectomy.[20]
Side effects
Causes severe side effects that can not be tolerated on daily bases. Side effects include hypokalemia 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.