Abstract
Cyclin-dependent kinases 4 and 6 (CDK4/6), which are involved in dynamic regulation of cell cycle, play an indispensable role in controlling the tumor growth. Here, based on the scaffold of palbociclib, we designed and synthesized a series of covalent CDK4/6 inhibitors that targeted amino acid Thr107. The optimized compound C-13 exhibited potent in vitro anticancer activity against CDK4/6 with high selectivity over CDK4/6. Moreover, C-13 showed significant tumor growth inhibition in MDA-MB-231 tumor xenograft model (TGI of 93.49% at dose of 40 mg/kg) without causing significant weight loss and toxicity during the treatment period.
Keywords:
CDK4; CDK6; Cell cycle; Covalent inhibitor; Palbociclib.
Copyright © 2021 Elsevier Masson SAS. All rights reserved.
MeSH terms
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Animals
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Apoptosis / drug effects
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Binding Sites
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Cell Cycle Checkpoints / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
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Cyclin-Dependent Kinase 4 / metabolism
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Cyclin-Dependent Kinase 6 / antagonists & inhibitors*
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Cyclin-Dependent Kinase 6 / metabolism
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Drug Design*
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Female
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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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Neoplasms / drug therapy
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Piperazines / chemistry*
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Piperazines / metabolism
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Piperazines / therapeutic use
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / metabolism
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Protein Kinase Inhibitors / therapeutic use
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Pyridines / chemistry*
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Pyridines / metabolism
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Pyridines / therapeutic use
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Xenograft Model Antitumor Assays
Substances
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Piperazines
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Protein Kinase Inhibitors
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Pyridines
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinase 6
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palbociclib