Abstract
The P21-activated kinases (PAK) are emerging antitumor therapeutic targets. In this paper, we describe the discovery of potent PAK inhibitors guided by structure-based drug design. In addition, the efflux of the pyrrolopyrazole series was effectively reduced by applying multiple medicinal chemistry strategies, leading to a series of PAK inhibitors that are orally active in inhibiting tumor growth in vivo.
MeSH terms
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Administration, Oral
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Amides / chemical synthesis
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Amides / pharmacokinetics
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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 / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Carbamates / chemistry
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Carbamates / pharmacokinetics
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Carbamates / pharmacology
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Crystallography, X-Ray
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Dogs
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Humans
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Hydrogen Bonding
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Mice
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Models, Molecular
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Molecular Conformation
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Permeability
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Pyrazoles / chemical synthesis*
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Pyrazoles / pharmacokinetics
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Pyrazoles / pharmacology
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Pyrroles / chemical synthesis*
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Pyrroles / pharmacokinetics
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Pyrroles / pharmacology
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Rats
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Stereoisomerism
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Structure-Activity Relationship
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Tumor Burden / drug effects
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Xenograft Model Antitumor Assays
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p21-Activated Kinases / antagonists & inhibitors*
Substances
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Amides
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Antineoplastic Agents
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Carbamates
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Pyrazoles
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Pyrroles
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p21-Activated Kinases