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.

6‐shogaol induces apoptosis and enhances radiosensitivity in head and neck squamous cell carcinoma cell lines

“…Mcl‐1 is an antiapoptotic protein that belongs to the Bcl‐2 family. It is over‐expressed in many cancer cell types leading to resistance to apoptosis as well as to resistance of chemo‐ and radiotherapies (Beekman & Howell, ). Recently, inhibition of Mcl‐1 via small molecule inhibitors has become of interest (Belmar & Fesik, ).…”

“…Error bars represent the standard error of the mean. Data for 6 Gy not shown to resistance to apoptosis as well as to resistance of chemo-and radiotherapies (Beekman & Howell, 2016 Considering that treatment options for head and neck cancer include radio-and chemotherapy, the combinatorial effect of 6-shogaol with irradiation and cisplatin was examined. A combination of treatment modalities often leads to major side effects and a significant reduction in quality of life.…”

Peptide‐Directed Binding for the Discovery of Modulators of α‐Helix‐Mediated Protein–Protein Interactions: Proof‐of‐Concept Studies with the Apoptosis Regulator Mcl‐1

“…Ar ecent review on Mcl-1 inhibitors highlights that less than thirty compounds have been reported with comparable selectivity for Mcl-1. [28] Further studies are underway to structurally confirm the binding sites of the hybrid and small-molecule compounds generated from peptide-directed binding.I ti se xpected that peptide-directed binding is applicable to other a-helical PPIs,s uch as the p53/hDM2 interaction, the Bcl-x L /BIM interaction, or the HIV gp41 hexameric coiled-coil fusion complex. [29] …”

“…Ar ecent review on Mcl-1 inhibitors highlights that less than thirty compounds have been reported with comparable selectivity for Mcl-1. [28] Further studies are underway to structurally confirm the binding sites of the hybrid and…”

Peptide‐Directed Binding for the Discovery of Modulators of α‐Helix‐Mediated Protein–Protein Interactions: Proof‐of‐Concept Studies with the Apoptosis Regulator Mcl‐1

“…Importantly, these compounds are able to mimic the selectivity of the natural scaffold. A recent review on Mcl‐1 inhibitors highlights that less than thirty compounds have been reported with comparable selectivity for Mcl‐1 28. Further studies are underway to structurally confirm the binding sites of the hybrid and small‐molecule compounds generated from peptide‐directed binding.…”