Hot-Spots of Mcl-1 Protein

Protein-protein interactions (PPIs) control many important physiological processes within human cells. Apoptosis or programmed cell death is closely regulated by pro- and antiapoptotic signals. Dysregulation of this homeostasis is implicated in tumorigenesis and acquired resistance to treatments. Th...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2020-02, Vol.63 (3), p.928-943
Main Authors: Denis, Camille, Sopková-de Oliveira Santos, Jana, Bureau, Ronan, Voisin-Chiret, Anne Sophie
Format: Article
Language:English
Subjects:
Chemical Sciences
Medicinal Chemistry
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Summary:Protein-protein interactions (PPIs) control many important physiological processes within human cells. Apoptosis or programmed cell death is closely regulated by pro- and antiapoptotic signals. Dysregulation of this homeostasis is implicated in tumorigenesis and acquired resistance to treatments. The emerging importance of Mcl-1 protein in chemotherapeutic resistance makes it a high priority therapeutic target. Targeting PPIs associated with Mcl-1 presents many challenges for the design of inhibitors. This review focuses on the characterization of the Mcl-1 hot-spots which are related to four hydrophobic pockets P1-P4 and one major electrostatic interaction. Analysis of structural data highlights the high importance of the P2/P3 pockets for the binding of nonpeptide ligands. In order to guide medicinal chemists into making more selective and potent Mcl-1 inhibitors, the Mcl-1 protein is compared to other antiapoptotic proteins.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.9b00983