Discovery and development of Seliciclib. How systems biology approaches can lead to better drug performance

Abstract

Seliciclib (R-Roscovitine) was identified as an inhibitor of CDKs and has undergone drug development and clinical testing as an anticancer agent. In this review, the authors describe the discovery of Seliciclib and give a brief summary of the biology of the CDKs Seliciclib inhibits. An overview of the published in vitro and in vivo work supporting the development as an anti-cancer agent, from in vitro experiments to animal model studies ending with a summary of the clinical trial results and trials underway is presented. In addition some potential non-oncology applications are explored and the potential mode of action of Seliciclib in these areas is described. Finally the authors argue that optimisation of the therapeutic effects of kinase inhibitors such as Seliciclib could be enhanced using a systems biology approach involving mathematical modelling of the molecular pathways regulating cell growth and division.

Targeting CDKs with Roscovitine Increases Sensitivity to DNA Damaging Drugs of Human Osteosarcoma Cells

“…The mammalian cell cycle is mainly controlled by CDKs, the activity of which is modulated by several activators (cyclins) and inhibitors. CDKs activity is commonly altered in cancer cells, and several human neoplasms present increased CDKs expression, indicating that these kinases are essential or play a relevant role for tumour growth and proliferation [5, 6]. …”

“…In particular, CDK2 has proved to be deregulated in various malignancies, thus appearing as a relevant factor for the uncontrolled proliferation of tumour cells [5, 6, 10–13]. …”

“…One of the most studied of these inhibitors is roscovitine (marketed as seliciclib or CYC202; Cyclacell Pharmaceuticals Inc, Berkeley Heights, NJ), a 2,6,9-tri-substituted purine analogue of olomoucine that competes with ATP for its binding site on CDK2 and other CDKs [4–6, 10, 23–25]. Seliciclib has been tested in Phase I and II clinical trials for haematologic and solid tumours, showing some promising results and indicating that combination therapies with conventional chemotherapeutic drugs were more effective than monotherapy regimens [2, 4–6, 21, 25–27]. …”

Cdk5 disruption attenuates tumor PD-L1 expression and promotes antitumor immunity

“…Cdk5-specific kinase activity could be abolished in vitro by roscovitine, a nonselective inhibitor against Cdks 1,2,5,7, and 9 (fig. S1B) (10). To interrogate Cdk5-specific functions, we disrupted Cdk5 in wild-type murine MB cells (MM1WT) by short hairpin-mediated RNA interference (MM1 shCdk5) and clustered regularly interspaced short palindromic repeats (CRISPR)–Cas9–targeted mutation (MM1 crCdk5), with nontargeting constructs as controls (MM1 shNS and MM1 crNeg).…”

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.…”