Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 63, Issue 3, Pages 928-943Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.9b00983
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Funding
- Normandy County Council, European Union
- Normandy County Council
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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.
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