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

  • J Med Chem. 2018 Sep 13;61(17):7785-7795. doi: 10.1021/acs.jmedchem.8b00765.
Shuai Liu  1 ,  Hailemichael O Yosief  1 ,  Lingling Dai  2 ,  He Huang  3 ,  Gagan Dhawan  1  4 ,  Xiaofeng Zhang  1 ,  Alex M Muthengi  1 ,  Justin Roberts ,  Dennis L Buckley ,  Jennifer A Perry ,  Lei Wu ,  James E Bradner  5 ,  Jun Qi  6 ,  Wei Zhang  1
Affiliations
  • 1. Department of Chemistry , University of Massachusetts-Boston , Boston , Massachusetts 02125 , United States.
  • 2. Phase I Clinical Trial Center & Department of Clinical Pharmacology, Xiangya Hospital , Central South University , Changsha , Hunan 410008 , P.R. China.
  • 3. Department of Chemistry , Stony Brook University , Stony Brook , New York 11794-3400 , United States.
  • 4. Department of Biomedical Science, Acharya Narendra Dev College , University of Delhi , New Delhi 110019 , India.
  • 5. Novartis Institutes for Biomedical Research , Cambridge , Massachusetts 02139 , United States.
  • 6. Department of Medicine , Harvard Medical School , Boston , Massachusetts 02115 , United States.
PMID: 30125504 DOI: 10.1021/acs.jmedchem.8b00765
Abstract

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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