Differential Water Networks Guide Selectivity Optimization of a Cell Active BPTF Inhibitor in Neuroblastoma
Bromodomain PHD finger Transcription Factor (BPTF) is an epigenetic regulator implicated in cancer progression. However, despite its oncogenic significance, highly selective and potent inhibitors of the BPTF bromodomain (BRD) with suitable physicochemical properties are lacking. Previously, we reported BZ1, a submicromolar BPTF inhibitor that has off-target activities. Here, we applied comparative structural biology and molecular modeling to design BZ2, a regioisomer of BZ1 with enhanced selectivity for BPTF over other class I BRDs and class-IV BRDs such as BRD7 and BRD9. Crystal structures and computational analyses reveal that differential engagement of water networks and polar interactions drives this selectivity. Functional studies demonstrate that genetic disruption of the BPTF BRD or treatment with BZ2 suppresses neuroblastoma (NB) cell growth. With high potency and improved physicochemical properties, BZ2 provides a valuable tool for probing the biology of BPTF and represents a promising starting point for advancing BPTF-targeted drug development.
Authors
- Priyanka Samanta (ORCID: https://orcid.org/0000-0001-9127-5816)
- Sourav Das (ORCID: https://orcid.org/0000-0003-1759-0345)
- Marcus Fischer (ORCID: https://orcid.org/0000-0002-7179-2581)
- Molly Sneddon (ORCID: https://orcid.org/0000-0002-7249-3401)
- Timothy R. Stachowski (ORCID: https://orcid.org/0000-0002-6097-4857)
- William C. K. Pomerantz (ORCID: https://orcid.org/0000-0002-0163-4078)
- Stanley Nithianantham (ORCID: https://orcid.org/0000-0001-6238-647X)
- Caroline R. Buchholz (ORCID: https://orcid.org/0000-0001-5293-7215)
- Wenwei Lin (ORCID: https://orcid.org/0000-0001-8754-6150)
- Anang A. Shelat (ORCID: https://orcid.org/0000-0002-6266-2910)
- Anasuya Pal
- Yongtao Li (ORCID: https://orcid.org/0000-0003-0083-2328)
- Shi Zhang (ORCID: https://orcid.org/0000-0002-5406-4224)
- Liying Fan (ORCID: https://orcid.org/0000-0001-9699-617X)
- Chi-Ming Tsou (ORCID: https://orcid.org/0009-0005-9528-1080)
- Kesavan Babu
- Xiang Fu (714580)
- Rahul S. Kathayat (ORCID: https://orcid.org/0000-0002-9159-2413)
- Taosheng Chen
- Lei Yang
Institutions
- University of Minnesota (US)
- St. Jude Children's Research Hospital (US)
Publication Details
- Journal
- Angewandte Chemie International Edition
- Published
- 2026-09-08
- DOI
- https://doi.org/10.1002/anie.4580510
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- U.S. Department of Energy
- Georgia Research Alliance
- American Lebanese Syrian Associated Charities
- National Institutes of Health
- Office of Science
- National Institute of General Medical Sciences
- Biological and Environmental Research
- Argonne National Laboratory
- Brookhaven National Laboratory