Structural basis for potent inhibition of the Aurora kinases and a T315I multi-drug resistant mutant form of Abl kinase by VX-680

Abstract The small molecule inhibitor of the Aurora-family of protein kinases VX-680 or MK-0457, demonstrates potent anti-cancer activity in multiple in vivo models and has recently entered phase II clinical trials. Although VX-680 shows a high degree of enzyme selectivity against multiple kinases,...

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Bibliographic Details
Published in:Cancer letters 2007-06, Vol.251 (2), p.323-329
Main Authors: Cheetham, G.M.T, Charlton, P.A, Golec, J.M.C, Pollard, J.R
Format: Article
Language:English
Subjects:
Aurora kinase
Aurora Kinases
Bcr-Abl
Benzamides
Binding sites
Cancer
Cell cycle
Clinical trials
Competition
Crystal structure
Drug design
Drug Resistance, Neoplasm - genetics
Enzymes
Hematology, Oncology and Palliative Medicine
Imatinib Mesylate
Kinases
Leukaemia
Mitosis
Models, Molecular
Mutation
Piperazines - pharmacology
Protein Conformation
Protein Kinase Inhibitors - pharmacology
Protein Serine-Threonine Kinases - chemistry
Protein Serine-Threonine Kinases - metabolism
Proteins
Proto-Oncogene Proteins c-abl - genetics
Proto-Oncogene Proteins c-abl - metabolism
Pyrimidines - pharmacology
VX-680
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Summary:Abstract The small molecule inhibitor of the Aurora-family of protein kinases VX-680 or MK-0457, demonstrates potent anti-cancer activity in multiple in vivo models and has recently entered phase II clinical trials. Although VX-680 shows a high degree of enzyme selectivity against multiple kinases, it unexpectedly inhibits both Flt-3 and Abl kinases at low nanomolar concentrations. Furthermore VX-680 potently inhibits Abl and the Imatinib resistant mutant (T315I) that is commonly expressed in refractory CML and ALL. We describe here the crystal structure of VX-680 bound to Aurora-A and show that this inhibitor exploits a centrally located hydrophobic pocket in the active site that is only present in an inactive or “closed” kinase conformation. A tight association of VX-680 with this hydrophobic pocket explains its high affinity for the Aurora kinases and also provides an explanation for its selectivity profile, including its ability to inhibit Abl and the Imatinib-resistant mutant (T315I).
ISSN:0304-3835
1872-7980
DOI:10.1016/j.canlet.2006.12.004