9ZUK

Crystal structure of BPTF bromodomain bound to BZ1

This is a non-PDB format compatible entry.

Summary for 9ZUK

• Entry DOI: 10.2210/pdb9zuk/pdb
• Descriptor: Nucleosome-remodeling factor subunit BPTF, 5-[4-(2-aminoethyl)anilino]-4-chloro-2-methylpyridazin-3(2H)-one (3 entities in total)
• Functional Keywords: bromodomain, inhibitor, cancer, bptf, nurf, chromatin remodeling, gene regulation
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 29468.30

Authors

Babu, K.,Stachowski, T.R.,Fischer, M. (deposition date: 2025-12-24, release date: 2026-09-16, Last modification date: 2026-11-11)

Primary citation

Babu, K.,Tsou, C.J.,Das, S.,Fan, L.,Pal, A.,Sneddon, M.,Stachowski, T.R.,Samanta, P.,Nithianantham, S.,Buchholz, C.,Zhang, S.,Fu, X.,Kathayat, R.S.,Lin, W.,Li, Y.,Yang, L.,Chen, T.,Fischer, M.,Shelat, A.A.,Pomerantz, W.C.K.
Differential Water Networks Guide Selectivity Optimization of a Cell Active BPTF Inhibitor in Neuroblastoma.
Angew.Chem.Int.Ed.Engl., 65:-, 2026

PubMed 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.

PubMed: 42711825
DOI: 10.1002/anie.4580510

Experimental method

X-RAY DIFFRACTION (1.35 Å)