New Design Rules for Developing Potent Cell-Active Inhibitors of the Nucleosome Remodeling Factor (NURF) via BPTF Bromodomain Inhibition

The nucleosome remodeling factor (NURF) alters chromatin accessibility through interactions with its largest subunit,the bromodomain PHD finger transcription factor BPTF. BPTF is overexpressed in several cancers and is an emerging anticancer target. Targeting the BPTF bromodomain presents a potentia...

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Published in:Journal of medicinal chemistry Vol. 64; no. 18; pp. 13902 - 13917
Main Authors: Zahid, Huda, Buchholz, Caroline R., Singh, Manjulata, Ciccone, Michael F., Chan, Alice, Nithianantham, Stanley, Shi, Ke, Aihara, Hideki, Fischer, Marcus, Schonbrunn, Ernst, dos Santos, Camila O., Landry, Joseph W., Pomerantz, William C. K.
Format: Journal Article
Language:English
Published: WASHINGTON Amer Chemical Soc 23.09.2021
Subjects:
Amino Acid Sequence
Animals
Antigens, Nuclear - chemistry
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Antineoplastic Agents - toxicity
Cell Line, Tumor
Chemistry, Medicinal
Drug Design
Life Sciences & Biomedicine
Mice
Molecular Structure
Nerve Tissue Proteins - antagonists & inhibitors
Nerve Tissue Proteins - chemistry
Pharmacology & Pharmacy
Protein Domains
Pyridazines - chemistry
Pyridazines - pharmacology
Pyridazines - toxicity
Science & Technology
Structure-Activity Relationship
Transcription Factors - antagonists & inhibitors
Transcription Factors - chemistry
GENE
CANCER
GROWTH
ISSN:0022-2623, 1520-4804, 1520-4804
Online Access:Get more information
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Summary:The nucleosome remodeling factor (NURF) alters chromatin accessibility through interactions with its largest subunit,the bromodomain PHD finger transcription factor BPTF. BPTF is overexpressed in several cancers and is an emerging anticancer target. Targeting the BPTF bromodomain presents a potential strategy for its inhibition and the evaluation of its functional significance; however, inhibitor development for BPTF has lagged behind those of other bromodomains. Here we describe the development of pyridazinone-based BPTF inhibitors. The lead compound, BZ1, possesses a high potency (K-d = 6.3 nM) and >350-fold selectivity over BET bromodomains. We identify an acidic triad in the binding pocket to guide future designs. We show that our inhibitors sensitize 4T1 breast cancer cells to doxorubicin but not BPTF knockdown cells, suggesting a specificity to BPTF. Given the high potency and good physicochemical properties of these inhibitors, we anticipate that they will be useful starting points for chemical tool development to explore the biological roles of BPTF.
Bibliography:NIH RePORTER
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ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/acs.jmedchem.1c01294