title: Fragment-Based, Structure-Enabled Discovery of Novel Pyridones and Pyridone Macrocycles as Potent Bromodomain and Extra-Terminal Domain (BET) Family Bromodomain Inhibitors.
abstract: Members of the BET family of bromodomain containing proteins have been identified as potential targets for blocking proliferation in a variety of cancer cell lines. A two-dimensional NMR fragment screen for binders to the bromodomains of BRD4 identified a phenylpyridazinone fragment with a weak binding affinity (1, Ki= 160 μM). SAR investigation of fragment 1, aided by X-ray structure-based design, enabled the synthesis of potent pyridone and macrocyclic pyridone inhibitors exhibiting single digit nanomolar potency in both biochemical and cell based assays. Advanced analogs in these series exhibited high oral exposures in rodent PK studies and demonstrated significant tumor growth inhibition efficacy in mouse flank xenograft models.
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Le
authors.initials: L
authors.lastname: Wang
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: John K
authors.identifier: 0000-0003-2611-8480
authors.initials: JK
authors.lastname: Pratt
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Todd
authors.initials: T
authors.lastname: Soltwedel
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: George S
authors.initials: GS
authors.lastname: Sheppard
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Fidanze
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Dachun
authors.initials: D
authors.lastname: Liu
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Hasvold
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Mantei
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: James H
authors.initials: JH
authors.lastname: Holms
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: William J
authors.initials: WJ
authors.lastname: McClellan
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Wendt
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Carol
authors.initials: C
authors.lastname: Wada
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Robin
authors.initials: R
authors.lastname: Frey
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: T Matthew
authors.initials: TM
authors.lastname: Hansen
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Hubbard
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Chang H
authors.initials: CH
authors.lastname: Park
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Leiming
authors.initials: L
authors.lastname: Li
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Terrance J
authors.initials: TJ
authors.lastname: Magoc
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Albert
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Lin
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Warder
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Kovar
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Huang
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Denise
authors.initials: D
authors.lastname: Wilcox
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Rongqi
authors.initials: R
authors.lastname: Wang
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Rajaraman
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Petros
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Charles W
authors.initials: CW
authors.lastname: Hutchins
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Sanjay C
authors.initials: SC
authors.lastname: Panchal
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Chaohong
authors.initials: C
authors.lastname: Sun
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Elmore
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Yu
authors.initials: Y
authors.lastname: Shen
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Warren M
authors.initials: WM
authors.lastname: Kati
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Keith F
authors.initials: KF
authors.lastname: McDaniel
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D047028:Macrocyclic Compounds / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D015394:Molecular Structure; D011728:Pyridones / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D047028:Macrocyclic Compounds; D011728:Pyridones