title: Small-Molecule and Peptide Inhibitors of the Pro-Survival Protein Mcl-1.
abstract: The ability of protein-protein interactions to regulate cellular processes in both beneficial and detrimental ways has made them obvious drug targets. The Bcl-2 family of proteins undergo a series of protein-protein interactions which regulate the intrinsic cell-death pathway. The pro-survival members of the Bcl-2 family, including Bcl-2, Bcl-xL , and Mcl-1, are commonly overexpressed in a number of human cancers. Effective modulators of members of the Bcl-2 family have been developed and are undergoing clinical trials, but the efficient modulation of Mcl-1 is still not represented in the clinic. In addition, Mcl-1 is a major cause of resistance to radio- and chemotherapies, including inhibitors that target other Bcl-2 family members. Subsequently, the inhibition of Mcl-1 has become of significant interest to the scientific community. This review covers the progress made to date in modulating the activity of Mcl-1, by both stapled peptides and small molecules. The development of peptides as drug candidates, and the advancement of experimental and computational techniques used to discover small molecules are also highlighted.
authors.affiliation: School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, Norfolk, NR4 7TJ, UK.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Beekman
authors.affiliation: School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, Norfolk, NR4 7TJ, UK. L.Howell@uea.ac.uk.
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Howell
mesh_terms: D055808:Drug Discovery; D006801:Humans; D015394:Molecular Structure; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010455:Peptides; D054852:Small Molecule Libraries
keywords: Bcl-2; Mcl-1; protein-protein interactions; small-molecule inhibitors; stapled peptides