Abstract
The functions of the bromodomain and extra terminal (BET) family of proteins have been implicated in a wide range of diseases, particularly in the oncology and immuno-inflammatory areas, and several inhibitors are under investigation in the clinic. To mitigate the risk of attrition of these compounds due to structurally related toxicity findings, additional molecules from distinct chemical series were required. Here we describe the structure- and property-based optimization of the in vivo tool molecule I-BET151 toward I-BET282E, a molecule with properties suitable for progression into clinical studies.
MeSH terms
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Animals
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Anti-Inflammatory Agents / chemical synthesis
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Anti-Inflammatory Agents / metabolism
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Anti-Inflammatory Agents / therapeutic use*
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Arthritis / chemically induced
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Arthritis / drug therapy*
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Collagen
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Crystallography, X-Ray
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Dogs
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Female
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Imidazoles / chemical synthesis
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Imidazoles / metabolism
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Imidazoles / therapeutic use*
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Male
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Mice
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Molecular Structure
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Nuclear Proteins / antagonists & inhibitors*
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Nuclear Proteins / chemistry
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Nuclear Proteins / metabolism
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Protein Binding
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Protein Domains
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Quinolines / chemical synthesis
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Quinolines / metabolism
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Quinolines / therapeutic use*
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Rats
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Rats, Inbred Lew
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Rats, Wistar
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Structure-Activity Relationship
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Transcription Factors / antagonists & inhibitors*
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Transcription Factors / chemistry
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Transcription Factors / metabolism
Substances
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Anti-Inflammatory Agents
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Brd4 protein, mouse
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Brd4 protein, rat
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Imidazoles
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Nuclear Proteins
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Quinolines
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Transcription Factors
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Collagen