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Structure-Guided Design and Development of Potent and Selective Dual Bromodomain 4 (BRD4)/Polo-like Kinase 1 (PLK1) Inhibitors

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posted on 20.08.2018, 00:00 by Shuai Liu, Hailemichael O. Yosief, Lingling Dai, He Huang, Gagan Dhawan, Xiaofeng Zhang, Alex M. Muthengi, Justin Roberts, Dennis L. Buckley, Jennifer A. Perry, Lei Wu, James E. Bradner, Jun Qi, Wei Zhang
The simultaneous inhibition of polo-like kinase 1 (PLK1) and BRD4 bromodomain by a single molecule could lead to the development of an effective therapeutic strategy for a variety of diseases in which PLK1 and BRD4 are implicated. Compound 23 has been found to be a potent dual kinase–bromodomain inhibitor (BRD4-BD1 IC50 = 28 nM, PLK1 IC50 = 40 nM). Compound 6 was found to be the most selective PLK1 inhibitor over BRD4 in our series (BRD4-BD1 IC50 = 2579 nM, PLK1 IC50 = 9.9 nM). Molecular docking studies with 23 and BRD4-BD1/PLK1 as well as with 6 corroborate the biochemical assay results.

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