Abstract
The discovery and potency optimization of a series of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1 is described. Micromolar hits taken from high-throughput screening were optimized for biochemical and cellular mechanistic potency to ~10nM, as exemplified by compound 12az. Application of structure-based drug design aided by co-crystal structures of TAK1 with inhibitors significantly shortened the number of iterations required for the optimization.
Keywords:
7-Amino-furo[2,3-c]pyridine; Cancer; Inflammation; Inhibitors; TAK1.
Copyright © 2013 Elsevier Ltd. All rights reserved.
MeSH terms
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Amines / chemical synthesis
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Amines / chemistry
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Amines / pharmacology
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Animals
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Crystallography, X-Ray
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Drug Design
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Enzyme Activation / drug effects
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology
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Furans / chemical synthesis
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Furans / chemistry
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Furans / pharmacology
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Humans
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Inhibitory Concentration 50
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MAP Kinase Kinase Kinases / antagonists & inhibitors*
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Mice
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Molecular Structure
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Neoplasms / drug therapy
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Pyridines* / chemical synthesis
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Pyridines* / pharmacokinetics
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Pyridines* / pharmacology
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
Substances
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Amines
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Enzyme Inhibitors
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Furans
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Pyridines
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MAP Kinase Kinase Kinases
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MAP kinase kinase kinase 7