Background: Anti-apoptotic members of the Bcl-2 family of proteins are upregulated
in a majority of cancers and are potential therapeutic targets. Fragment-based design led
to the development of clinical candidates that target Bcl-xL/Bcl-2. Although these BclxL/
Bcl-2 inhibitors showed promise in pre-clinical studies, resistance to several Bcl-xL inhibitors
was observed, when used alone. This is attributed to the over-expression of Mcl-1,
another member of the Bcl-2 family of proteins. Indeed, Mcl-1 is highly amplified in numerous
cancers, suggesting that it may contribute to malignant cell growth and evasion of apoptosis.
Therefore, significant efforts have been made toward the development of direct Mcl-1 inhibitors
for cancer therapy.
Methods: Following an extensive search of peer-reviewed articles on the development of
Mcl-1-selective inhibitors, the literature retrieved is chronologically arranged and discussed in
this review article.
Results: We have included 147 articles in this review; including articles that describe the development
of stapled peptides with improved binding affinity as Mcl-1-selective BH3 mimetics,
those describing fragment-based and structure-based design of small molecule Mcl-1 inhibitors
by various research groups, and those detailing the use of natural products and their
derivatives as potential Mcl-1 inhibitors.
Conclusion: The therapeutic potential of targeting the Mcl-1 protein for cancer drug discovery
is vast. Stapling BH3 peptides, as well as the development of small molecule inhibitors as
BH3 mimetics, are viable strategies to develop selective Mcl-1 inhibitors. With no clinically
approved candidate in hand, additional modes of perturbing the biological function of this
protein will aid drug discovery efforts.