Abstract
BMX is a member of the TEC family of nonreceptor tyrosine kinases. We have used structure-based drug design in conjunction with kinome profiling to develop a potent, selective, and irreversible BMX kinase inhibitor, BMX-IN-1, which covalently modifies Cys496. BMX-IN-1 inhibits the proliferation of Tel-BMX-transformed Ba/F3 cells at two digit nanomolar concentrations but requires single digit micromolar concentrations to inhibit the proliferation of prostate cancer cell lines. Using a combinatorial kinase inhibitor screening strategy, we discovered that the allosteric Akt inhibitor, MK2206, is able to potentiate BMX inhibitor's antiproliferation efficacy against prostate cancer cells.
Publication types
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Letter
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / isolation & purification
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Antineoplastic Agents / pharmacology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Combinatorial Chemistry Techniques
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Drug Discovery*
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Flow Cytometry
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Humans
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Inhibitory Concentration 50
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Male
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Models, Molecular
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Prostatic Neoplasms / drug therapy*
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / isolation & purification
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Protein Kinase Inhibitors / pharmacology*
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Pyridones / chemistry*
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Pyridones / isolation & purification
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Pyridones / pharmacology*
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Sulfonamides / chemistry*
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Sulfonamides / isolation & purification
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Sulfonamides / pharmacology*
Substances
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Antineoplastic Agents
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BMX-IN-1
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Protein Kinase Inhibitors
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Pyridones
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Sulfonamides
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BMX protein, human
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Protein-Tyrosine Kinases