Abstract
Inhibition of the bromodomain and extra-terminal (BET) family of adaptor proteins is an attractive strategy for targeting transcriptional regulation of key oncogenes, such as c-MYC. Starting with the screening hit 1, a combination of structure-activity relationship and protein structure-guided drug design led to the discovery of a differently oriented carbazole 9 with favorable binding to the tryptophan, proline, and phenylalanine (WPF) shelf conserved in the BET family. Identification of an additional lipophilic pocket and functional group optimization to optimize pharmacokinetic (PK) properties culminated in the discovery of 18 (BMS-986158) with excellent potency in binding and functional assays. On the basis of its favorable PK profile and robust in vivo activity in a panel of hematologic and solid tumor models, BMS-986158 was selected as a candidate for clinical evaluation.
MeSH terms
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Administration, Oral
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Carbazoles / administration & dosage
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Carbazoles / chemistry
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Carbazoles / pharmacology*
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Cell Cycle Proteins / antagonists & inhibitors
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Cell Cycle Proteins / metabolism
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Dose-Response Relationship, Drug
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Drug Discovery*
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Humans
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Molecular Structure
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Phenylalanine / administration & dosage
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Phenylalanine / chemistry
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Phenylalanine / pharmacology*
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Proline / administration & dosage
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Proline / chemistry
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Proline / pharmacology*
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Structure-Activity Relationship
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / metabolism
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Tryptophan / administration & dosage
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Tryptophan / chemistry
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Tryptophan / pharmacology*
Substances
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Antineoplastic Agents
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BRD2 protein, human
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BRD4 protein, human
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Carbazoles
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Cell Cycle Proteins
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Transcription Factors
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carbazole
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Phenylalanine
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Tryptophan
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Proline