Abstract
Selective inhibition of exclusively transcription-regulating PTEFb/CDK9 is a promising new approach in cancer therapy. Starting from lead compound BAY-958, lead optimization efforts strictly focusing on kinase selectivity, physicochemical and DMPK properties finally led to the identification of the orally available clinical candidate atuveciclib (BAY 1143572). Structurally characterized by an unusual benzyl sulfoximine group, BAY 1143572 exhibited the best overall profile in vitro and in vivo, including high efficacy and good tolerability in xenograft models in mice and rats. BAY 1143572 is the first potent and highly selective PTEFb/CDK9 inhibitor to enter clinical trials for the treatment of cancer.
Keywords:
CDK; PTEFb; antitumor agents; drug design; sulfoximines.
© 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Binding Sites
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Cell Line, Tumor
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Cell Survival / drug effects
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Crystallography, X-Ray
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Cyclin-Dependent Kinase 9 / antagonists & inhibitors*
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Cyclin-Dependent Kinase 9 / metabolism
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Half-Life
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HeLa Cells
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Humans
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Leukemia, Myeloid, Acute / drug therapy
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Mice
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Mice, Nude
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Molecular Conformation
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Molecular Docking Simulation
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Neoplasms / drug therapy*
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Neoplasms / pathology
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / therapeutic use*
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Protein Kinase Inhibitors / toxicity
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Protein Structure, Tertiary
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Rats
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Rats, Nude
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Structure-Activity Relationship
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Sulfonamides / chemistry
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Sulfonamides / therapeutic use*
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Sulfonamides / toxicity
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Transplantation, Heterologous
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Triazines / chemistry
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Triazines / therapeutic use*
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Triazines / toxicity
Substances
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Protein Kinase Inhibitors
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Sulfonamides
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Triazines
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atuveciclib
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Cyclin-Dependent Kinase 9