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Issue 24, 2016
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Structure-based design of 3-carboxy-substituted 1,2,3,4-tetrahydroquinolines as inhibitors of myeloid cell leukemia-1 (Mcl-1)

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Abstract

Mcl-1 has recently emerged as an attractive target to expand the armamentarium in the war on cancer. Using structure-based design, 3-carboxy-substituted 1,2,3,4-tetrahydroquinolines were developed as a new chemotype to inhibit the Mcl-1 oncoprotein. The most potent compound inhibited Mcl-1 with a Ki of 120 nM, as determined by a fluorescence polarization competition assay. Direct binding was confirmed by 2D 1H–15N HSQC NMR spectroscopy with 15N-Mcl-1, which indicated that interactions with R263 and T266, and occupation of the p2 pocket are likely responsible for the potent binding affinity. The short and facile synthetic chemistry to access target molecules is expected to mediate lead optimization.

Graphical abstract: Structure-based design of 3-carboxy-substituted 1,2,3,4-tetrahydroquinolines as inhibitors of myeloid cell leukemia-1 (Mcl-1)

  • This article is part of the themed collection: New Talent
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Publication details

The article was received on 06 Oct 2015, accepted on 09 Dec 2015 and first published on 10 Dec 2015


Article type: Communication
DOI: 10.1039/C5OB02063H
Author version available: Download Author version (PDF)
Citation: Org. Biomol. Chem., 2016,14, 5505-5510
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    Structure-based design of 3-carboxy-substituted 1,2,3,4-tetrahydroquinolines as inhibitors of myeloid cell leukemia-1 (Mcl-1)

    L. Chen, P. T. Wilder, B. Drennen, J. Tran, B. M. Roth, K. Chesko, P. Shapiro and S. Fletcher, Org. Biomol. Chem., 2016, 14, 5505
    DOI: 10.1039/C5OB02063H

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