A pharmacodynamic model of Aurora kinase inhibitors in the spindle assembly checkpoint. / Mistry, Hitesh B.; MacCallum, David E.; Jackson, Robert C.; Chaplain, Mark A. J.; Davidson, Fordyce A.
In: Frontiers in Bioscience, Vol. 15, No. 1, 2010, p. 249-258.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A pharmacodynamic model of Aurora kinase inhibitors in the spindle assembly checkpoint
A1 - Mistry,Hitesh B.
A1 - MacCallum,David E.
A1 - Jackson,Robert C.
A1 - Chaplain,Mark A. J.
A1 - Davidson,Fordyce A.
AU - Mistry,Hitesh B.
AU - MacCallum,David E.
AU - Jackson,Robert C.
AU - Chaplain,Mark A. J.
AU - Davidson,Fordyce A.
PY - 2010
Y1 - 2010
N2 - 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.
AB - 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.
KW - Spindle assembly checkpoint
KW - Aurora kinase
U2 - 10.2741/3619
DO - 10.2741/3619
M1 - Article
JO - Frontiers in Bioscience
JF - Frontiers in Bioscience
SN - 1093-9946
IS - 1
VL - 15
SP - 249
EP - 258
ER -