title: Methylpyrrole inhibitors of BET bromodomains.
abstract: An NMR fragment screen for binders to the bromodomains of BRD4 identified 2-methyl-3-ketopyrroles 1 and 2. Elaboration of these fragments guided by structure-based design provided lead molecules with significant activity in a mouse tumor model. Further modifications to the methylpyrrole core provided compounds with improved properties and enhanced activity in a mouse model of multiple myeloma.
authors.affiliation: AbbVie Inc., Oncology Discovery, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Hasvold
authors.affiliation: AbbVie Inc., Oncology Discovery, 1 North Waukegan Rd., North Chicago, IL 60064, USA. Electronic address: george.s.sheppard@abbvie.com.
authors.forename: George S
authors.initials: GS
authors.lastname: Sheppard
authors.affiliation: AbbVie Inc., Oncology Discovery, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Le
authors.initials: L
authors.lastname: Wang
authors.affiliation: AbbVie Inc., Oncology Discovery, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Fidanze
authors.affiliation: AbbVie Inc., Oncology Discovery, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Dachun
authors.initials: D
authors.lastname: Liu
authors.affiliation: AbbVie Inc., Oncology Discovery, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: John K
authors.initials: JK
authors.lastname: Pratt
authors.affiliation: AbbVie Inc., Oncology Discovery, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Mantei
authors.affiliation: AbbVie Inc., Oncology Discovery, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Carol K
authors.initials: CK
authors.lastname: Wada
authors.affiliation: AbbVie Inc., Oncology Discovery, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Robbert
authors.initials: R
authors.lastname: Hubbard
authors.affiliation: AbbVie Inc., Oncology Discovery, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Shen
authors.affiliation: AbbVie Inc., Oncology Discovery, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Lin
authors.affiliation: AbbVie Inc., Oncology Discovery, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Huang
authors.affiliation: AbbVie Inc., Oncology Discovery, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Warder
authors.affiliation: AbbVie Inc., Oncology Discovery, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Denise
authors.initials: D
authors.lastname: Wilcox
authors.affiliation: AbbVie Inc., Oncology Discovery, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Leiming
authors.initials: L
authors.lastname: Li
authors.affiliation: AbbVie Inc., Oncology Discovery, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: F Greg
authors.initials: FG
authors.lastname: Buchanan
authors.affiliation: AbbVie Inc., Oncology Discovery, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Smithee
authors.affiliation: AbbVie Inc., Oncology Discovery, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Albert
authors.affiliation: AbbVie Inc., Oncology Discovery, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Terrance J
authors.initials: TJ
authors.lastname: Magoc
authors.affiliation: AbbVie Inc., Oncology Discovery, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Chang H
authors.initials: CH
authors.lastname: Park
authors.affiliation: AbbVie Inc., Oncology Discovery, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Petros
authors.affiliation: AbbVie Inc., Oncology Discovery, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Sanjay C
authors.initials: SC
authors.lastname: Panchal
authors.affiliation: AbbVie Inc., Oncology Discovery, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Chaohong
authors.initials: C
authors.lastname: Sun
authors.affiliation: AbbVie Inc., Oncology Discovery, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Kovar
authors.affiliation: AbbVie Inc., Oncology Discovery, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Nirupama B
authors.initials: NB
authors.lastname: Soni
authors.affiliation: AbbVie Inc., Oncology Discovery, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Elmore
authors.affiliation: AbbVie Inc., Oncology Discovery, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Warren M
authors.initials: WM
authors.lastname: Kati
authors.affiliation: AbbVie Inc., Oncology Discovery, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Keith F
authors.initials: KF
authors.lastname: McDaniel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D006207:Half-Life; D006801:Humans; D051379:Mice; D056004:Molecular Dynamics Simulation; D009101:Multiple Myeloma / Q000188:drug therapy; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014183:Transplantation, Heterologous; D000092468:Bromodomain Containing Proteins
chemical_list: D000970:Antineoplastic Agents; D009687:Nuclear Proteins; D011758:Pyrroles; D014157:Transcription Factors; C486694:Brd4 protein, mouse; D000092468:Bromodomain Containing Proteins
keywords: BET proteins; Bromodomain; Fragment screening