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.

Keywords: Bcl-2; Mcl-1; protein-protein interactions; small-molecule inhibitors; stapled peptides.

Figure 1

Fmoc‐protected amino acid building block and the BID SAHB_A hydrocarbon‐stapled peptide.