Abstract
The bromodomain and extra-terminal (BET) family proteins, consisting of BRD2, BRD3, BRD4, and testis-specific BRDT members, are epigenetic "readers" and play a key role in the regulation of gene transcription. BET proteins are considered to be attractive therapeutic targets for cancer and other human diseases. Recently, heterobifunctional small-molecule BET degraders have been designed based upon the proteolysis targeting chimera (PROTAC) concept to induce BET protein degradation. Herein, we present our design, synthesis, and evaluation of a new class of PROTAC BET degraders. One of the most promising compounds, 23, effectively degrades BRD4 protein at concentrations as low as 30 pM in the RS4;11 leukemia cell line, achieves an IC50 value of 51 pM in inhibition of RS4;11 cell growth and induces rapid tumor regression in vivo against RS4;11 xenograft tumors. These data establish that compound 23 (BETd-260/ZBC260) is a highly potent and efficacious BET degrader.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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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 / pharmacology*
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Cell Cycle Proteins
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Cell Line, Tumor
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Dose-Response Relationship, Drug
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Drug Design
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Drug Screening Assays, Antitumor / methods
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Female
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Humans
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Indoles / chemical synthesis
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Indoles / chemistry*
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Indoles / pharmacology*
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Leukemia / drug therapy
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Mice, SCID
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Nuclear Proteins / chemistry
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Nuclear Proteins / metabolism*
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Protein Serine-Threonine Kinases / metabolism
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Proteolysis
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry*
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Pyrimidines / pharmacology*
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RNA-Binding Proteins / metabolism
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology
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Structure-Activity Relationship
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Transcription Factors / chemistry
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Transcription Factors / metabolism*
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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BRD2 protein, human
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BRD3 protein, human
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BRD4 protein, human
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Cell Cycle Proteins
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Indoles
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Nuclear Proteins
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Pyrimidines
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RNA-Binding Proteins
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Small Molecule Libraries
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Transcription Factors
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Protein Serine-Threonine Kinases