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Structural Basis for the Synthesis of Indirubins as Potent and Selective Inhibitors of Glycogen Synthase Kinase-3 and Cyclin-Dependent Kinases

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    Structural Basis for the Synthesis of Indirubins as Potent and Selective Inhibitors of Glycogen Synthase Kinase-3 and Cyclin-Dependent Kinases
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    Laboratory of Pharmacognosy and Laboratory of Pharmaceutical Chemistry, Department of Pharmacy, University of Athens, Panepistimiopolis Zografou, GR-15771 Athens, Greece, Structural Biology Unit, Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milano, Italy, 3, Centre for Structural Biology, Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, U.K., C.N.R.S., Cell Cycle Group, Station Biologique, B.P. 74, 29682 ROSCOFF Cedex, Bretagne, France, and Laboratory of Molecular & Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, New York 10021
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2004, 47, 4, 935–946
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    https://doi.org/10.1021/jm031016d
    Published January 8, 2004
    Copyright © 2004 American Chemical Society
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    Abstract

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    Pharmacological inhibitors of glycogen synthase kinase-3 (GSK-3) and cyclin-dependent kinases have a promising potential for applications against several neurodegenerative diseases such as Alzheimer's disease. Indirubins, a family of bis-indoles isolated from various natural sources, are potent inhibitors of several kinases, including GSK-3. Using the cocrystal structures of various indirubins with GSK-3β, CDK2 and CDK5/p25, we have modeled the binding of indirubins within the ATP-binding pocket of these kinases. This modeling approach provided some insight into the molecular basis of indirubins' action and selectivity and allowed us to forecast some improvements of this family of bis-indoles as kinase inhibitors. Predicted molecules, including 6-substituted and 5,6-disubstituted indirubins, were synthesized and evaluated as CDK and GSK-3 inhibitors. Control, kinase-inactive indirubins were obtained by introduction of a methyl substitution on N1.

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    †

     University of Athens.

    *

     Corresponding authors:  A. L. Skaltsounis (tel:  +3210 7274598, fax:  +3210 7274594, e-mail:  [email protected]) or L. Meijer (e-mail:  [email protected]).

    ‡

     European Institute of Oncology.

    §

     Chester Beatty Laboratories.

    ‖

     C.N.R.S.

    ⊥

     The Rockefeller University.

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2004, 47, 4, 935–946
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    https://doi.org/10.1021/jm031016d
    Published January 8, 2004
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