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

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

  • J Med Chem. 2021 Sep 23;64(18):13902-13917. doi: 10.1021/acs.jmedchem.1c01294.
Huda Zahid 1,  Caroline R Buchholz 2,  Manjulata Singh 3,  Michael F Ciccone 4,  Alice Chan 5,  Stanley Nithianantham 6,  Ke Shi 7,  Hideki Aihara 7,  Marcus Fischer 6,  Ernst Schönbrunn 5,  Camila O Dos Santos 4,  Joseph W Landry 3,  William C K Pomerantz 1 2
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States.
  • 2 Department of Medicinal Chemistry, University of Minnesota, 308 Harvard Street SE, Minneapolis, Minnesota 55455, United States.
  • 3 The Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298, United States.
  • 4 Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, United States.
  • 5 Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, Florida 33612, United States.
  • 6 Department of Chemical Biology & Therapeutics and Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
  • 7 Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, 321 Church Street SE, Minneapolis, Minnesota 55455, United States.
PMID: 34515477 DOI: 10.1021/acs.jmedchem.1c01294
Abstract

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 (Kd = 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.

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