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

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

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.

Figures
Products