Using a mammalian cell cycle simulation to interpret differential kinase inhibition in anti-tumour pharmaceutical development.
Systems biology needs to show practical relevance to commercial biological challenges such as those of pharmaceutical development. The aim of this work is to design and validate some applications in anti-cancer therapeutic development. The test system was a group of novel cyclin-dependent kinase (CDK) inhibitors synthesised by Cyclacel Ltd. The measured in vitro IC50s of each compound were used as input data to a proprietary cell cycle model developed by Physiomics plc. The model was able to predict over three orders of magnitude the cytotoxicity of each compound without model adaptation to specific cancer cell types. This pattern matched the experimentally determined data. One class of compounds was predicted to cause an increase of the cell cycle length with a non-linear dose-response curve. Further work will use apoptosis and DNA replication simulations to look at overall cell effects.
Chassagnole
C
C
Physiomics plc, Magdalen Centre, Oxford Science Park, Oxford OX4 4GA, UK. cchassagnole@physiomics-plc.com
Jackson
R C
RC
Hussain
N
N
Bashir
L
L
Derow
C
C
Savin
J
J
Fell
D A
DA
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D002453:Cell Cycle / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004360:Drug Therapy, Computer-Assisted / Q000379:methods; D006801:Humans; D007928:Lethal Dose 50; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011687:Purines / Q000008:administration & dosage*; D000077546:Roscovitine; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011687:Purines; D000077546:Roscovitine