Abstract
The dysfunctional bromodomain PHD finger transcription factor (BPTF) exerts a pivotal influence in the occurrence and development of many human diseases, particularly cancers. Herein, through the structural decomposition of the reported BPTF inhibitor TP-238, the effective structural fragments were synthetically modified to obtain our lead compound DC-BPi-03. DC-BPi-03 was identified as a novel BPTF-BRD inhibitor with a moderate potency (IC50 = 698.3 ± 21.0 nM). A structure-guided structure-activity relationship exploration gave rise to two BPTF inhibitors with much higher affinities, DC-BPi-07 and DC-BPi-11. Notably, DC-BPi-07 and DC-BPi-11 show selectivities 100-fold higher than those of other BRD targets. The cocrystal structures of BPTF in complex with DC-BPi-07 and DC-BPi-11 demonstrate the rationale of chemical efforts from the atomic level. Further study showed that DC-BPi-11 significantly inhibited leukemia cell proliferation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antigens, Nuclear / chemistry
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Antigens, Nuclear / metabolism
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Drug Discovery
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Drug Screening Assays, Antitumor
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G1 Phase Cell Cycle Checkpoints / drug effects
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Humans
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Indoles / chemical synthesis
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Indoles / metabolism
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Indoles / pharmacology*
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Molecular Structure
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Nerve Tissue Proteins / antagonists & inhibitors*
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Nerve Tissue Proteins / chemistry
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Nerve Tissue Proteins / metabolism
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Protein Binding
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Protein Domains
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Pyrimidines / chemical synthesis
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Pyrimidines / metabolism
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Pyrimidines / pharmacology*
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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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Antigens, Nuclear
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Antineoplastic Agents
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Indoles
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Nerve Tissue Proteins
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Pyrimidines
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Transcription Factors
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fetal Alzheimer antigen