SAR and inhibitor complex structure determination of a novel class of potent and specific Aurora kinase inhibitors

Heron, Nicola M.; Anderson, Malcolm; Blowers, David P.; Breed, J.; Eden, Jonathan; Green, Stephen; Hill, George B.; Johnson, Trevor; Jung, F.; McMiken, Helen; Mortlock, Andrew A.; Pannifer, Andrew; Pauptit, Richard A.; Pink, Jennifer H.; Roberts, Nicola; Rowsell, Siân

doi:10.1016/j.bmcl.2005.11.053

Cited by 127 publications

(106 citation statements)

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“…The preference for five membered rings can be helpful to support the findings of the 3D-CoMFA model, which suggest a bulkier substituent in this position. The structure-activity relationships of the pyridino-and pyrimidinoquinazoline compounds have been described recently and include one of the first crystal structures with a small inhibitor bound to the Aurora kinase [45] . It was helpful in rationalizing the observed high potency and high specificity for the Aurora kinases.…”

Section: Discussionmentioning

confidence: 99%

“…A number of crystal structures of Aurora A in different conformations with ATP analogues have been published [45][46][47][48] . A crystal structure of Aurora A complexed with a small molecule inhibitor from the pyrimidinoquinazoline series adopts an inactive conformation with the displacement of the DFG motif (DFG-out) [45] .…”

Section: Discussionmentioning

confidence: 99%

“…A crystal structure of Aurora A complexed with a small molecule inhibitor from the pyrimidinoquinazoline series adopts an inactive conformation with the displacement of the DFG motif (DFG-out) [45] . In the crystal structure ( Figure 5), the distance between the carbonyl oxygen (black skeleton) and the hydrogen of the amino group was 1.8 Å.…”

Section: Discussionmentioning

confidence: 99%

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Structural studies of B-type Aurora kinase inhibitors using computational methods

et al. 2010

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Structural studies of B-type Aurora kinase inhibitors using computational methods

et al. 2010

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“…1(b) and 1(c)). 36,37 The half maximum inhibitory activity (IC 50 ) values were 0.8 nM and 2100 nM against on Aurora A for HPM and 2JZ, respectively. In this paper, we carried out relatively long time scale molecular dynamics (MD) simulations, followed by molecular mechanics/PoissonÀBoltzmann surface area (MM/PBSA) free energy calculations 38À41 and molecular mechanics/ generalized Born surface area (MM/GBSA) free energy decomposition analysis 42,43 to investigate the binding mechanism of these two di®erent inhibitors and Aurora A with a contrasting binding a±nity.…”

Section: Introductionmentioning

confidence: 99%

“…The two X-ray crystallographic structures of inhibitorÀAurora A complexes were obtained form the RCSB Protein Data Bank (PDB id: 2C6E, 3HA6) 36,37 and were used for the computational study. All crystal water molecules were kept in the initial structure.…”

Section: Preparing the Starting Structurementioning

confidence: 99%

Understanding the Molecular Mechanism of Binding Modes of Aurora a Inhibitors by Long Time Scale Gpu Dynamics

Xiu

et al. 2013

J. Theor. Comput. Chem.

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Inhibition of Aurora A kinase interaction is considered to be a promissing approach for the discovery of new molecularly targeted cancer therapeutics. In this study, the binding mechanisms of two di®erent inhibitors with a contrasting binding a±nity to Aurora A were investigated by long time scale GPU molecular dynamics (MD) simulations coupled with molecular mechanics-PoissonÀBoltzmann/generalized Born surface area (MM-PB/GBSA) method. The results showed that the predicted binding free energies of these two complexes were consistent with the experimental data. Through analyzing the individual energy components of binding free energy, we found that the van der Waals contribution was the main force to drive the inhibitorÀprotein binding and the electrostatic contribution was also a crucial factor for the inhibitorÀAurora A binding. The structural analysis demonstrated that the inhibitor HPM could produce more hydrophobic interaction contacts with Aurora A than that of 2JZ, and the loss of key hydrogen bonds between the inhibitor and residue Arg137 in the hinge region of † † Corresponding authors.

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Kinase Inhibitors: Approved Drugs and Clinical Candidates

Bradbury

2010

Burger's Medicinal Chemistry and Drug Discovery

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During the past two decades, protein kinases involved in a wide range of cellular signaling pathways have proved a tractable class of oncology drug target, and by the end of 2008 nine small‐molecule kinase inhibitors had been approved by regulatory authorities for treatment of human hematological or solid tumors. The majority of protein kinase inhibitors that have progressed to clinical evaluation target the adenosine triphosphate binding site. After a brief overview of design of the pioneering Bcr‐Abl kinase inhibitor imatinib, this chapter is structured around the effect of kinase inhibitor drugs on the “hallmarks of cancer,” the acquired cellular capabilities that collectively promote malignant growth of solid tumors. The chapter continues by reviewing growth factor and antiangiogenic kinase inhibitors, approaches that have now been validated in large‐scale clinical trials, and then proceeds to discuss inhibitors implicated in the cell cycle, survival signaling, and tissue invasion and metastasis. Reviewed in the chapter are approximately 20 oncology kinase drug targets and 60 associated inhibitors with disclosed chemical structures that have been approved by regulatory authorities or are undergoing clinical trials. Synopses of evolution from lead to candidate drug distilled from original articles illustrate themes in kinase inhibitor medicinal chemistry.

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SAR and inhibitor complex structure determination of a novel class of potent and specific Aurora kinase inhibitors

Cited by 127 publications

References 10 publications

Structural studies of B-type Aurora kinase inhibitors using computational methods

Structural studies of B-type Aurora kinase inhibitors using computational methods

Understanding the Molecular Mechanism of Binding Modes of Aurora a Inhibitors by Long Time Scale Gpu Dynamics

Kinase Inhibitors: Approved Drugs and Clinical Candidates

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