Abstract
Most traditional cytotoxic anticancer agents ablate the rapidly dividing epithelium of the hair follicle and induce alopecia (hair loss). Inhibition of cyclin-dependent kinase 2 (CDK2), a positive regulator of eukaryotic cell cycle progression, may represent a therapeutic strategy for prevention of chemotherapy-induced alopecia (CIA) by arresting the cell cycle and reducing the sensitivity of the epithelium to many cell cycle-active antitumor agents. Potent small-molecule inhibitors of CDK2 were developed using structure-based methods. Topical application of these compounds in a neonatal rat model of CIA reduced hair loss at the site of application in 33 to 50% of the animals. Thus, inhibition of CDK2 represents a potentially useful approach for the prevention of CIA in cancer patients.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Retracted Publication
MeSH terms
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Alopecia / chemically induced*
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Alopecia / prevention & control*
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Animals
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Animals, Newborn
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Antineoplastic Agents / toxicity*
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Antineoplastic Combined Chemotherapy Protocols / toxicity
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Apoptosis / drug effects
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CDC2-CDC28 Kinases*
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Cell Cycle / drug effects
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Cell Line
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinases / antagonists & inhibitors*
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Cyclin-Dependent Kinases / metabolism
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Cyclophosphamide / toxicity
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Cytoprotection / drug effects
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DNA / biosynthesis
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Doxorubicin / toxicity
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Drug Design
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Epithelium / drug effects
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Etoposide / toxicity
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Hair Follicle / cytology
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Hair Follicle / drug effects*
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Humans
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Indoles / chemical synthesis
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Indoles / chemistry
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Indoles / pharmacology*
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Mice
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Mice, SCID
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Phosphorylation
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Rats
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Retinoblastoma Protein / metabolism
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Scalp / transplantation
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Sulfonamides / chemical synthesis
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Sulfonamides / chemistry
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Sulfonamides / pharmacology*
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Transplantation, Heterologous
Substances
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2-(4-((6,7-dihydro-7-oxo-5H-thiazolo(5,4-e)indol-8-ylidene)amino)phenylsulfamido)pyridine
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Antineoplastic Agents
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Enzyme Inhibitors
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Indoles
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Retinoblastoma Protein
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Sulfonamides
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Etoposide
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Doxorubicin
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Cyclophosphamide
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DNA
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Protein Serine-Threonine Kinases
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CDC2-CDC28 Kinases
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CDK2 protein, human
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Cdk2 protein, mouse
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Cdk2 protein, rat
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinases