Abstract
The identification of a novel series of Aurora kinase inhibitors and exploitation of their SAR is described. Replacement of the initial quinazoline core with a pyrimidine scaffold and modification of substituents led to a series of very potent inhibitors of cellular proliferation. MK-0457 (VX-680) has been assessed in Phase II clinical trials in patients with treatment-refractory chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) containing the T315I mutation.
MeSH terms
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Aurora Kinases
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Cell Line, Tumor
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Computer Simulation
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Crystallography, X-Ray
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Drug Design
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Humans
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
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Mutant Proteins / antagonists & inhibitors
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Mutant Proteins / metabolism
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Piperazines / chemistry*
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Piperazines / pharmacology
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacology
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Structure-Activity Relationship
Substances
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Mutant Proteins
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Piperazines
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Protein Kinase Inhibitors
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tozasertib
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Aurora Kinases
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Protein Serine-Threonine Kinases