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J Med Chem. 2018 Sep 13;61(17):7785-7795. doi: 10.1021/acs.jmedchem.8b00765. Epub 2018 Aug 30.

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

Author information

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.

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.

PMID:
30125504
PMCID:
PMC6309379
DOI:
10.1021/acs.jmedchem.8b00765
[Indexed for MEDLINE]
Free PMC Article

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