Abstract
Simultaneous inhibition of the bromodomain and extra-terminal domain and Aurora kinases is a promising anticancer therapeutic strategy. Based on our previous study on BET-kinase dual inhibitors, we employed the molecular docking approach to design novel dual BET-Aurora kinase A inhibitors. Through several rounds of optimization and with the guidance of the solved cocrystal structure of BRD4 bound to inhibitor 27, we finally obtained a series of highly potent dual BET-Aurora kinase A inhibitors. Compound 38 exhibited strong affinity toward both BRD4 and Aurora kinase A. It also showed good antiproliferative activities on diverse cancer cell lines, good pharmacokinetic profiles, and favorable antitumor efficacy in renal cell cancer and colon cancer xenograft models with TGI of 45.99% and 53.06%, respectively. The development of compound 38 reinforces the concept that a rational design may achieve dual inhibitors targeting specific kinases and bromodomain proteins.
MeSH terms
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Animals
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Antineoplastic Agents* / chemical synthesis
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Antineoplastic Agents* / chemistry
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Antineoplastic Agents* / pharmacology
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Antineoplastic Agents* / therapeutic use
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Aurora Kinase A* / antagonists & inhibitors
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Aurora Kinase A* / metabolism
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Bromodomain Containing Proteins
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Cell Cycle Proteins / antagonists & inhibitors
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Drug Design*
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Humans
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Mice
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Mice, Nude
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Molecular Docking Simulation*
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / metabolism
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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 Kinase Inhibitors* / therapeutic use
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Structure-Activity Relationship
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / metabolism
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Xenograft Model Antitumor Assays
Substances
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Protein Kinase Inhibitors
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Antineoplastic Agents
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Aurora Kinase A
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BRD4 protein, human
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Transcription Factors
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Cell Cycle Proteins
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Nuclear Proteins
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Bromodomain Containing Proteins