Abstract
Potent, trans-2-(pyridin-3-yl)cyclopropanecarboxamide-containing inhibitors of the human nicotinamide phosphoribosyltransferase (NAMPT) enzyme were identified using fragment-based screening and structure-based design techniques. Multiple crystal structures were obtained of initial fragment leads, and this structural information was utilized to improve the biochemical and cell-based potency of the associated molecules. Many of the optimized compounds exhibited nanomolar antiproliferative activities against human tumor lines in in vitro cell culture experiments. In a key example, a fragment lead (13, KD = 51 μM) was elaborated into a potent NAMPT inhibitor (39, NAMPT IC50 = 0.0051 μM, A2780 cell culture IC50 = 0.000 49 μM) which demonstrated encouraging in vivo efficacy in an HT-1080 mouse xenograft tumor model.
MeSH terms
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Amides / chemical synthesis*
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Amides / chemistry
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Amides / pharmacology
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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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Cell Line, Tumor
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Crystallography, X-Ray
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Cyclopropanes / chemical synthesis*
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Cyclopropanes / chemistry
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Cyclopropanes / pharmacology
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Drug Screening Assays, Antitumor
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Heterografts
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Humans
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Mice
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Mice, Nude
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Models, Molecular
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Neoplasm Transplantation
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Nicotinamide Phosphoribosyltransferase / antagonists & inhibitors*
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Protein Conformation
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Pyridines / chemical synthesis*
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Pyridines / chemistry
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Pyridines / pharmacology
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Stereoisomerism
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Structure-Activity Relationship
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Sulfones / chemical synthesis*
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Sulfones / chemistry
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Sulfones / pharmacology
Substances
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Amides
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Antineoplastic Agents
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Cyclopropanes
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N-(4-((1-propyl-1H-pyrazol-4-yl)sulfonyl)phenyl)-2-(pyridin-3-yl)cyclopropanecarboxamide
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Pyridines
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Sulfones
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Nicotinamide Phosphoribosyltransferase