BAZ2A is a large multidomain protein overexpressed in aggressive prostate cancer, where it potentiates migration and invasion of other tissues. To counteract its metastasis-promoting role, small molecules interfering with the recognition of acetylated lysines by the BAZ2A bromodomain have been identified. However, unlike other bromodomains, BAZ2A has a shallow pocket, which significantly complicates the development of potent inhibitors. Here, we report the exploration of the acetyl-pyrrole scaffold, leading to the identification of BAZ2A-binding compounds assuming a peculiar, almost enclosed, conformation, as determined by X-ray crystallography. These molecules pose the basis for the development of potent BAZ2A macrocyclic inhibitors, as performed for other bromodomains.
BT - Acta Crystallographica Section D, Structural Biology C1 - 0321 DA - 2026 Jul 01 DO - 10.1107/S2059798326004596 IS - 7 J2 - Acta Crystallogr D Struct Biol LA - eng M3 - Research Article N2 -BAZ2A is a large multidomain protein overexpressed in aggressive prostate cancer, where it potentiates migration and invasion of other tissues. To counteract its metastasis-promoting role, small molecules interfering with the recognition of acetylated lysines by the BAZ2A bromodomain have been identified. However, unlike other bromodomains, BAZ2A has a shallow pocket, which significantly complicates the development of potent inhibitors. Here, we report the exploration of the acetyl-pyrrole scaffold, leading to the identification of BAZ2A-binding compounds assuming a peculiar, almost enclosed, conformation, as determined by X-ray crystallography. These molecules pose the basis for the development of potent BAZ2A macrocyclic inhibitors, as performed for other bromodomains.
PY - 2026 SP - 1 EP - 9 T2 - Acta Crystallographica Section D, Structural Biology TI - Unusual Backfolded Binding Poses of BAZ2A Bromodomain Binders UR - https://journals.iucr.org/d/issues/2026/07/00/chr5011/index.html VL - 82 ER -