A pharmacodynamic model of Aurora kinase inhibitors in the spindle assembly checkpoint.
Arguably the most dramatic phase in the cell cycle is mitosis, during which replicated chromosomes are sorted into two distinct sets. Aurora kinases are central to the accurate segregation of chromosomes during mitosis. Consequently, they have been selected as possible targets for cancer therapy. Anti-cancer drugs that target Aurora kinases are normally designed to inhibit their function. The complexity of the roles of Aurora kinases and their interaction with respective inhibitors means that it is often very difficult to obtain meaningful links between inhibitor concentration and efficacy using standard methods. To overcome these difficulties, we propose a novel mathematical modelling approach. We present a pharmacodynamic model that is able to encapsulate the key roles of two kinases, Aurora A and B, in the spindle assembly checkpoint. Moreover, the model is capable of qualitatively differentiating between the effects of inhibiting Aurora A, Aurora B and A plus B, respectively, by predicting cell behaviour. Consequently, predictions regarding the qualitative relationship between inhibitors, measurable biomarkers and cell damage can be obtained using this powerful modelling approach.
Mistry
Hitesh B
HB
Division of Mathematics, University of Dundee, Dundee DD1 4HN, Scotland, UK.
MacCallum
David E
DE
Jackson
Robert C
RC
Chaplain
Mark A J
MA
Davidson
Fordyce A
FA
D000465:Algorithms; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D064107:Aurora Kinase B; D064127:Aurora Kinases; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D018386:Kinetochores / Q000187:drug effects / Q000378:metabolism; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008941:Spindle Apparatus / Q000187:drug effects* / Q000378:metabolism
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases