Water network differences steer a more selective BPTF bromodomain inhibitor that suppresses neuroblastoma cell growth
- Comparative structural analysis and modeling yielded BZ2, a regioisomer of an earlier BPTF bromodomain inhibitor with off-target activity.
- Crystal structures and calculations attribute improved selectivity against other bromodomains, including BRD7 and BRD9, to differing water networks and polar contacts.
- Both genetic bromodomain disruption and BZ2 treatment curbed neuroblastoma cell growth, positioning it as a probe and lead.
💡 Points Based on the abstract
A regioisomer swap buying selectivity against BRD7 and BRD9 is the kind of cheap, tractable win I'd happily take: no new scaffold, just moving a substituent so it exploits a water network the off-targets can't match. That's a transferable trick for any bromodomain series. I'd still want the BZ2 selectivity panel beyond those two before calling it a probe.