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

Shuai Liu; Hailemichael O. Yosief; Lingling Dai; He Huang; Gagan Dhawan; Xiaofeng Zhang; Alex M. Muthengi; Justin Roberts; Dennis L. Buckley; Jennifer A. Perry; Lei Wu; James E. Bradner; Jun Qi; Wei Zhang

doi:10.1021/acs.jmedchem.8b00765

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

Shuai Liu
, Hailemichael O. Yosief
, Lingling Dai
, He Huang
, Gagan Dhawan
, Xiaofeng Zhang
, Alex M. Muthengi
, Justin Roberts
, Dennis L. Buckley
, Jennifer A. Perry
, Lei Wu
, James E. Bradner
, Jun Qi
, Wei Zhang

Chemistry

University of Massachusetts Boston
Dana-Farber Cancer Institute
Central South University
Stony Brook University
University of Delhi
Novartis Institute of Biomedical Research
Harvard University

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	7785-7795
Number of pages	11
Journal	Journal of Medicinal Chemistry
Volume	61
Issue number	17
DOIs	https://doi.org/10.1021/acs.jmedchem.8b00765
State	Published - Sep 13 2018

ASJC Scopus Subject Areas

Molecular Medicine
Drug Discovery

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Liu, S., Yosief, H. O., Dai, L., Huang, H., Dhawan, G., Zhang, X., Muthengi, A. M., Roberts, J., Buckley, D. L., Perry, J. A., Wu, L., Bradner, J. E., Qi, J., & Zhang, W. (2018). Structure-Guided Design and Development of Potent and Selective Dual Bromodomain 4 (BRD4)/Polo-like Kinase 1 (PLK1) Inhibitors. Journal of Medicinal Chemistry, 61(17), 7785-7795. https://doi.org/10.1021/acs.jmedchem.8b00765

Liu, S, Yosief, HO, Dai, L, Huang, H, Dhawan, G, Zhang, X, Muthengi, AM, Roberts, J, Buckley, DL, Perry, JA, Wu, L, Bradner, JE, Qi, J & Zhang, W 2018, 'Structure-Guided Design and Development of Potent and Selective Dual Bromodomain 4 (BRD4)/Polo-like Kinase 1 (PLK1) Inhibitors', Journal of Medicinal Chemistry, vol. 61, no. 17, pp. 7785-7795. https://doi.org/10.1021/acs.jmedchem.8b00765

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

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.",

author = "Shuai Liu and Yosief, \{Hailemichael O.\} and Lingling Dai and He Huang and Gagan Dhawan and Xiaofeng Zhang and Muthengi, \{Alex M.\} and Justin Roberts and Buckley, \{Dennis L.\} and Perry, \{Jennifer A.\} and Lei Wu and Bradner, \{James E.\} and Jun Qi and Wei Zhang",

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doi = "10.1021/acs.jmedchem.8b00765",

language = "English",

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AU - Liu, Shuai

AU - Yosief, Hailemichael O.

AU - Dai, Lingling

AU - Huang, He

AU - Dhawan, Gagan

AU - Zhang, Xiaofeng

AU - Muthengi, Alex M.

AU - Roberts, Justin

AU - Buckley, Dennis L.

AU - Perry, Jennifer A.

AU - Wu, Lei

AU - Bradner, James E.

AU - Qi, Jun

AU - Zhang, Wei

PY - 2018/9/13

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

Abstract

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