Figure 10 summarizes the key conclusions from the preliminary studyand this current investigation. Amino acids that are critical for HER2ligand interaction include Lys724, Lys736, and Cys805. As illustrated in Figure 10, binding at the key amino acids results in blocking of the ATP binding site entrance, and may result in inhibition of HER2 activity. Analysis of the candidates indicates that carbonyl, carboxylic acid, and hydroxyl groups are critical moieties for stable binding. Based on the results of this study, the natural compound candidates have potential as biologically active compounds with improved stability in HER2. Designing HER2 inhibitors with carbonyl, carboxyl, and hydroxyl groups available for H-bond formation may improve protein-ligand stability. Mitotic kinases play crucial roles in regulation of cell division, yet aberrations in their expression and function are known to be involved in cancer initiation and progression. Targeting these kinases has proven in recent years to be an exciting avenue for alternative cancer therapies. The Aurora kinases have emerged as particularly promising targets due their roles in regulating multiple signalling pathways crucial for accurate cell division. Localization and function of each subtype �C Aurora A, B and C, has been studied and reviewed extensively in the recent literature. The association and implication of the Aurora kinases in cancer stems from early studies that revealed aberrant expression of both Aurora A and B in many solid and hematological malignancies. This association of Aurora kinase overexpression with a malignant phenotype has been functionally validated. Deregulation of the Aurora kinases disrupts mitotic processes crucial for accurate cell division leading to chromosomal instability and aneuploidyhowever a complete understanding of their role in tumourigenesis remains elusive. Reports of the role and function of Aurora A and B in leukaemia have been largely limited to expression studies in cell lines and small cohort clinical studies. Increased expression of Aurora A has been reported in many leukaemias, while the expression of Aurora B has shown no clear trend. Despite this, both Aurora A and B have been exploited as potential targets for therapeutic intervention. The promise of the Aurora kinases as anticancer targets has been such that small molecule inhibition as drug therapy is a rapidly Carfilzomib developing area of research. Early successful candidates in preclinical testing were pan-Aurora inhibitors such as VX-680, however it was shown that the dominant phenotype arising from these agents was that of Aurora B inhibition. Aurora B specific inhibitors such as AZD1152have since shown increasing promise and have reached early stage clinical trials against both solid and haematological malignancies. The earliest documented Aurora 
B inhibitor ZM447439 has also been well characterised as a probe of the cellular biology of Aurora B. Cellular OTX015 phenotypes of these agents such as inhibition of histone H3 phosphorylation, cytokinesis failure, and polyploidisation are consistent with inhibition of Aurora B. As yet, however, the specific factors that will influence sensitivity and resistance to Aurora kinase inhibitors have not been adequately addressed. A major drawback of molecularly targeted agents is the likelihood of acquired clinical resistance. Early success of the BCR-ABL kinase targeting drug Imatinib in the treatment of chronic myelogenous leukaemia was followed by the rapid emergence of clinical resistance. Resistance was discovered to be mediated by point mutations in the kinase domain preventing drug binding but maintaining catalytic activity.