title: BRD4 Structure-Activity Relationships of Dual PLK1 Kinase/BRD4 Bromodomain Inhibitor BI-2536.
abstract: A focused library of analogues of the dual PLK1 kinase/BRD4 bromodomain inhibitor BI-2536 was prepared and then analyzed for BRD4 and PLK1 inhibitory activities. Particularly, replacement of the cyclopentyl group with a 3-bromobenzyl moiety afforded the most potent BRD4 inhibitor of the series (39j) with a K i = 8.7 nM, which was equipotent against PLK1. The superior affinity of 39j over the parental compound to BRD4 possibly derives from improved interactions with the WPF shelf. Meanwhile, substitution of the pyrimidine NH with an oxygen atom reversed the PLK1/BRD4 selectivity to convert BI-2536 into a BRD4-selective inhibitor, likely owing to the loss of a critical hydrogen bond in PLK1. We believe further fine-tuning will furnish a BRD4 "magic bullet" or an even more potent PLK1/BRD4 dual inhibitor toward the expansion and improved efficacy of the chemotherapy arsenal.
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy , 20 North Pine Street, Baltimore, Maryland 21201, United States.
authors.forename: Lijia
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy , 20 North Pine Street, Baltimore, Maryland 21201, United States.
authors.forename: Jeremy L
authors.initials: JL
authors.lastname: Yap
authors.affiliation: ConverGene , 22 Firstfield Road, Gaithersburg, Maryland 20878, United States.
authors.forename: Makoto
authors.initials: M
authors.lastname: Yoshioka
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy , 20 North Pine Street, Baltimore, Maryland 21201, United States.
authors.forename: Maryanna E
authors.initials: ME
authors.lastname: Lanning
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy , 20 North Pine Street, Baltimore, Maryland 21201, United States.
authors.forename: Rachel N
authors.initials: RN
authors.lastname: Fountain
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy , 20 North Pine Street, Baltimore, Maryland 21201, United States.
authors.forename: Mithun
authors.initials: M
authors.lastname: Raje
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy , 20 North Pine Street, Baltimore, Maryland 21201, United States.
authors.forename: Jacob A
authors.initials: JA
authors.lastname: Scheenstra
authors.affiliation: ConverGene , 22 Firstfield Road, Gaithersburg, Maryland 20878, United States.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Strovel
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy , 20 North Pine Street, Baltimore, Maryland 21201, United States ; University of Maryland Greenebaum Cancer Center , 22 South Green Street, Baltimore, Maryland 21201, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Fletcher
keywords: BET; BI-2536; BRD; Bromodomain; kinase; protein−protein interaction