From Roscovitine to CYC202 to Seliciclib – from bench to bedside: discovery and development

Abstract

This monograph reviews the discovery and development of the cyclindependent kinase inhibitor roscovitine (R-roscovitine, CYC202, Seliciclib). The authors summarise the in vitro and in vivo data that have formed the basis for clinical investigation of Seliciclib as an anti-cancer drug. Kinase selectivity, cellular effects and the pharmacological properties of the drug are discussed in addition to the clinical results of Seliciclib being reviewed. Novel results on the effect of the drug in cardiac hypertrophy are summarized and potential applications of Seliciclib in other therapeutic areas, including, inflammation, virology, glomerulonephritis and polycystic kidney disease, are discussed. Finally the authors argue that optimisation of the therapeutic effect of kinase inhibitors such as Seliciclib can be enhanced using a systems biology approach involving mathematical modelling of the molecular pathways regulating cell growth and division. Seliciclib -discovery and developmentBioDiscovery 2 December 2013 | Issue 10 | 1

Human pluripotent stem-cell-derived cardiomyocytes in cardiovascular drug discovery and development

“…The use of Roscovitine, a drug known to inhibit CDK-related activity in tumour cells, has demonstrated positive results in the prevention of cardiac hypertrophy [24][25][26][27]. The results suggest that cardiac hypertrophy is accompanied by activation of CDK9, and that target based inhibitors of the kinase pathway may be suitable molecular targets for therapeutic intervention in HCM.…”

Methylene‐bearing sulfur‐containing cyanopyrimidine derivatives for treatment of cancer: Part‐II

“…It also contains four carbon aliphatic side chains. [ 23 ] 1,2,3‐Triazole‐cyanopyrimidine hybrids ( 1 ) reported by Li‐Ying et al, [ 24 ] replace “–NH” group at position‐2 of pyrimidine ring with isosteric sulfur‐bearing methylene linkage to evaluate their anticancer activity. Ma et al [ 25 ] reported methylene‐bearing sulfur‐containing cyanopyrimidine–thiourea hybrids ( 2 ) for their anticancer activity.…”

“…Further literature survey indicated that the presence of “–NH” or “–N” at position ortho to the cyano group alters the activity considerably. [ 23–26 ] Therefore, compounds bearing such patterns were also synthesized and evaluated for their anticancer activity and anti‐inflammatory potential. To study the biological target, compounds with good activity were also evaluated for their COX‐2 inhibition study.…”

Evaluation of the effectiveness of infusion of bone marrow derived cell in patients with heart failure: A network meta-analysis of randomized clinical trials and cohort studies

“…Stem cells have many uses in the treatment of various diseases such as spinal cord injury, hormonal impairment, various types of syndrome, infertility, chronic hepatitis, pancreatitis, diabetes mellitus, and ischemic heart diseases such as congestive heart failure, etc. ( 10 ). Different types of therapies for heart failure are subject to some limitations; for example, in many studies, inappropriate drug therapy is reported as the most common cause of exacerbating heart failure ( 11 ).…”