Abstract
The optimization of the dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-one R(2) and R(12) positions led to the identification of the first MLK1 and MLK3 subtype-selective inhibitors within the MLK family. Compounds 14 (CEP-5104) and 16 (CEP-6331) displayed good potency for MLK1 and MLK3 inhibition with a greater than 30- to 100-fold selectivity for related family members MLK2 and DLK. Compounds 14 and 16 were orally active in vivo in a mouse MPTP biochemical efficacy model that was comparable to the first-generation pan-MLK inhibitor 1 (CEP-1347). The MLK1 structure-activity relationships were supported by the first-reported X-ray crystal structure of MLK1 bound with 16.
MeSH terms
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Administration, Oral
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Animals
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Carbazoles / administration & dosage
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Carbazoles / chemistry
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Carbazoles / pharmacology*
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Cell Line, Tumor
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Crystallography, X-Ray
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Humans
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In Vitro Techniques
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MAP Kinase Kinase Kinases / antagonists & inhibitors*
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Magnetic Resonance Spectroscopy
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Mice
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Mitogen-Activated Protein Kinase Kinase Kinase 11
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Models, Molecular*
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Molecular Structure
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Pyrrolidinones / administration & dosage
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Pyrrolidinones / chemistry
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Pyrrolidinones / pharmacology*
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Rats
Substances
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2-isopropoxy-12-(2-hydroxyethyl)-13,14-dihydronaphthol(2,1-a)pyrrolo(3,4-c)carbazole-5-one
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2-methoxy-12-(2-hydroxyethyl)-13,14-dihydronaphthol(2,1-a)pyrrolo(3,4-c)carbazole-5-one
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Carbazoles
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Protein Kinase Inhibitors
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Pyrrolidinones
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MAP Kinase Kinase Kinases
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MAP3K9 protein, human