Abstract
The BRPF (bromodomain and PHD finger-containing) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Evaluation of the BRPF family as a potential drug target is at an early stage although there is an emerging understanding of a role in acute myeloid leukemia (AML). We report the optimization of fragment hit 5b to 13-d as a biased, potent inhibitor of the BRD of the BRPFs with excellent selectivity over nonclass IV BRD proteins. Evaluation of 13-d in a panel of cancer cell lines showed a selective inhibition of proliferation of a subset of AML lines. Pharmacokinetic studies established that 13-d had properties compatible with oral dosing in mouse models of disease (Fpo 49%). We propose that NI-42 (13-d) is a new chemical probe for the BRPFs suitable for cellular and in vivo studies to explore the fundamental biology of these proteins.
MeSH terms
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Adaptor Proteins, Signal Transducing / antagonists & inhibitors*
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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 / pharmacokinetics
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Antineoplastic Agents / pharmacology*
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Cell Line, Tumor
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DNA-Binding Proteins
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Drug Screening Assays, Antitumor
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Humans
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Leukemia, Myeloid, Acute / drug therapy
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Mice
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Microsomes, Liver / metabolism
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Nuclear Proteins / antagonists & inhibitors*
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Protein Domains
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Quinolones / chemical synthesis
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Quinolones / chemistry
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Quinolones / pharmacokinetics
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Quinolones / pharmacology*
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis
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Sulfonamides / chemistry
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Sulfonamides / pharmacokinetics
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Sulfonamides / pharmacology*
Substances
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4-cyano-N-(1,3-dimethyl-2-oxo-1,2-dihydroquinolin-6-yl)benzenesulfonamide
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Adaptor Proteins, Signal Transducing
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Antineoplastic Agents
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BRPF1 protein, human
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DNA-Binding Proteins
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Nuclear Proteins
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Quinolones
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Sulfonamides