title: Structure enabled design of BAZ2-ICR, a chemical probe targeting the bromodomains of BAZ2A and BAZ2B.
abstract: The bromodomain containing proteins BAZ2A/B play essential roles in chromatin remodeling and regulation of noncoding RNAs. We present the structure based discovery of a potent, selective, and cell active inhibitor 13 (BAZ2-ICR) of the BAZ2A/B bromodomains through rapid optimization of a weakly potent starting point. A key feature of the presented inhibitors is an intramolecular aromatic stacking interaction that efficiently occupies the shallow bromodomain pockets. 13 represents an excellent chemical probe for functional studies of the BAZ2 bromodomains in vitro and in vivo.
authors.affiliation: The Institute of Cancer Research, Division of Cancer Therapeutics, Cancer Research UK Cancer Therapeutics Unit , 15 Cotswold Road, Sutton, London SM2 5NG, U.K.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Drouin
authors.forename: Sally
authors.initials: S
authors.lastname: McGrath
authors.forename: Lewis R
authors.initials: LR
authors.lastname: Vidler
authors.forename: Apirat
authors.initials: A
authors.lastname: Chaikuad
authors.forename: Octovia
authors.initials: O
authors.lastname: Monteiro
authors.forename: Cynthia
authors.initials: C
authors.lastname: Tallant
authors.forename: Martin
authors.initials: M
authors.lastname: Philpott
authors.forename: Catherine
authors.initials: C
authors.lastname: Rogers
authors.forename: Oleg
authors.initials: O
authors.lastname: Fedorov
authors.forename: Manjuan
authors.initials: M
authors.lastname: Liu
authors.forename: Wasim
authors.initials: W
authors.lastname: Akhtar
authors.forename: Angela
authors.initials: A
authors.lastname: Hayes
authors.forename: Florence
authors.initials: F
authors.lastname: Raynaud
authors.forename: Susanne
authors.initials: S
authors.lastname: Müller
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.forename: Swen
authors.initials: S
authors.lastname: Hoelder
mesh_terms: D000818:Animals; D002868:Chromosomal Proteins, Non-Histone / Q000037:antagonists & inhibitors*; D015195:Drug Design; D051379:Mice; D008861:Microsomes / Q000187:drug effects*; D008958:Models, Molecular; D015335:Molecular Probes / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry* / Q000494:pharmacology*; D000092468:Bromodomain Containing Proteins
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D015335:Molecular Probes; D014230:Triazoles; C436708:BAZ2A protein, human; D000092468:Bromodomain Containing Proteins