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

Huda Zahid, Caroline R. Buchholz, Manjulata Singh, Michael F. Ciccone, Alice Chan, Stanley Nithianantham, Ke Shi, Hideki Aihara, Marcus Fischer, Ernst Schönbrunn, Camila O. dos Santos, Joseph W. Landry, William C.K. Pomerantz

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)13902-13917
Number of pages16
JournalJournal of medicinal chemistry
Volume64
Issue number18
DOIs
StatePublished - Sep 23 2021

Bibliographical note

Funding Information:
This work was conducted at the NE-CAT, GM/CA and SER-CAT beamlines at the Advanced Photon Source, which are supported by the NIH (P30-GM124165, Y1-CO-1020, and Y1-GM-1104). The Pilatus 6M detector on 24-ID-C beamline is funded by a NIH-ORIP HEI Grant (S10-RR029205). We thank staff at the NE-CAT, GM/CA, and SER-CAT beamlines for assistance in data collection. We thank the Moffitt Chemical Biology Core for use of the crystallization and crystallography facility (National Cancer Institute Grant P30-CA076292). The authors thank Jose Valentin Lopez for contributing to the synthesis of related compounds published here. Figures were created with BioRender and PyMOL. B and A were adapted with permission from Springer Nature, Applied Biophysics for Bromodomain Drug Discovery by William C. K. Pomerantz, Jorden A. Johnson, Peter D. Ycas, copyright 2019.

Funding Information:
This work was supported by the National Institute of General Medical Sciences R01GM121414-04 and R35 GM140837-01, a University of Minnesota IEM Engineering in Medicine Doctoral Fellowship 2020 (H.Z), a National Institutes of Health Chemistry-Biology Interface Training Grant 5T32GM132029-02 (C.R.B), a Department of Defense Grant W81XWH1910489 (J.W.L), and R35-GM118047 (H.A). M.F is supported by the American Lebanese Syrian Associated Charities (ALSAC) and R35Gm142772-01. C.O.D.S. is financially supported by the CSHL and Northwell Health affiliation, the NIH/NCI Grant R01CA248158-01, and the NIH/NIA Grant R01 AG069727-01.

Publisher Copyright:
© 2021 American Chemical Society

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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