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

Shuai LiuHailemichael O YosiefLingling DaiHe HuangGagan DhawanXiaofeng ZhangAlex M MuthengiJustin RobertsDennis L BuckleyJennifer A PerryLei WuJames E BradnerJun QiWei Zhang
Published in: Journal of medicinal chemistry (2018)
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.
Keyphrases
  • single molecule
  • molecular docking
  • photodynamic therapy
  • protein kinase
  • molecular dynamics simulations
  • high throughput
  • atomic force microscopy
  • case control