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

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.