Differential Water Networks Guide Selectivity Optimization of a Cell Active BPTF Inhibitor in Neuroblastoma
Year: 2026
Type: article
Abstract: 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.
Source: Angewandte Chemie
DOI: 10.1002/ange.4580510
Authors: Kesavan Babu, Chun‐Ju Tsou, Sourav Das, Liying Fan, Anasuya Pal, Molly Sneddon, Timothy R. Stachowski, Priyanka Samanta, Stanley Nithianantham, Caroline Buchholz, Shi Zhang, Xiang Fu, Rahul S. Kathayat, Wenwei Lin, Yongtao Li, Lei Yang, Taosheng Chen, Marcus Fischer, Anang A. Shelat, William C. K. Pomerantz
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,790
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
Awards: G102163711, G107546177, Chemical Probe Development for Epigenetic Complexes Enabled by Protein-Observed 19F NMR, G1285306620, G1313983767, G1633006425, G1664757510, G1699008898, G171842289, G1800737955, G1867732070, Phase II SER-CAT Optimization: Acquisition of a next generation area detector, G2004402655, G2287611682, G2302316395, G241279073, G262962599, G2857925935, G3067052642, G3075337988, G3262563802, G3338542329, Acquisition of a High Precision Micro Diffractometer to Support NIH funded Research at SER-CAT, G357145406, G3728080647, G409777406, G434509735, G4473831829, G498139845, G5535608740, G5607048534, G5746780444, G5765906131, G6153725424, G6476969910, G6800544485, G6848031779, G6918803902, G7463374569, G7932540327, G8701900045, G9000018909, G9000093951, Center for Biomolecular Structure (CBMS), Targeting the chromatin binding domains of BPTF for neuroblastoma epigenetic therapy, Training the Next Generation of Chemical Biologists, G952034259, Acquition of a microdiffractometer for SER-CAT, G969889393, G993149817
OpenAlex ID: W7212021272