9H-PurineScaffold RevealsInduced-Fit Pocket Plasticity of the BRD9 Bromodomain.
- Resource Type
- Article
- Authors
- Picaud, Sarah; Strocchia, Maria; Terracciano, Stefania; Lauro, Gianluigi; Mendez, Jacqui; Daniels, Danette L.; Riccio, Raffaele; Bifulco, Giuseppe; Bruno, Ines; Filippakopoulos, Panagis
- Source
- Journal of Medicinal Chemistry. Mar2015, Vol. 58 Issue 6, p2718-2736. 19p.
- Subject
- *ITERATIVE methods (Mathematics)
*CELL-mediated cytotoxicity
*BIOLUMINESCENCE
*HISTONES
*BIOLOGICAL assay
- Language
- ISSN
- 0022-2623
The 2-amine-9H-purinescaffold was identifiedas a weak bromodomain template and was developed via iterative structurebased design into a potent nanomolar ligand for the bromodomain ofhuman BRD9 with small residual micromolar affinity toward the bromodomainof BRD4. Binding of the lead compound 11to the bromodomainof BRD9 results in an unprecedented rearrangement of residues formingthe acetyllysine recognition site, affecting plasticity of the proteinin an induced-fit pocket. The compound does not exhibit any cytotoxiceffect in HEK293 cells and displaces the BRD9 bromodomain from chromatinin bioluminescence proximity assays without affecting the BRD4/histonecomplex. The 2-amine-9H-purine scaffold representsa novel template that can be further modified to yield highly potentand selective tool compounds to interrogate the biological role ofBRD9 in diverse cellular systems. [ABSTRACT FROM AUTHOR]