Abstract
Bromodomain containing proteins PB1, SMARCA4, and SMARCA2 are important components of SWI/SNF chromatin remodeling complexes. We identified bromodomain inhibitors that target these proteins and display unusual binding modes involving water displacement from the KAc binding site. The best compound binds the fifth bromodomain of PB1 with a KD of 124 nM, SMARCA2B and SMARCA4 with KD values of 262 and 417 nM, respectively, and displays excellent selectivity over bromodomains other than PB1, SMARCA2, and SMARCA4.
MeSH terms
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DNA Helicases / antagonists & inhibitors*
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DNA Helicases / metabolism
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DNA-Binding Proteins
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Dose-Response Relationship, Drug
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Humans
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Models, Molecular
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Molecular Structure
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Nuclear Proteins / antagonists & inhibitors*
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Nuclear Proteins / metabolism
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Pyrroles / chemical synthesis
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Pyrroles / chemistry
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Pyrroles / pharmacology*
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Quinazolinones / chemical synthesis
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Quinazolinones / chemistry
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Quinazolinones / pharmacology*
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Structure-Activity Relationship
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Transcription Factors / antagonists & inhibitors*
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Transcription Factors / metabolism
Substances
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6-chloro-3-((4-methylpiperazin-1-yl)methylene)-2,3-dihydropyrrolo(1,2-a)quinazolin-5(1H)-one
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DNA-Binding Proteins
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Nuclear Proteins
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PBRM1 protein, human
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Pyrroles
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Quinazolinones
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SMARCA2 protein, human
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Transcription Factors
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SMARCA4 protein, human
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DNA Helicases