CHAPTER 8: Discovery and Development of Mcl-1 Inhibitors as Anti-cancer Therapeutics: Hit to Clinical Candidate Optimization

Recent advances in drug screening and development strategies have accelerated the discovery of novel anti-cancer modalities. Targeting protein–protein interactions in particular has become a hot area in drug discovery and has enabled the ability to drug prominent therapeutic targets, such as the Bcl-2 family of apoptosis regulators. The Bcl-2 protein family member, Mcl-1, has emerged as a critical target across a vast array of cancers, playing a key role in preventing apoptosis. Many types of cancer rely on Mcl-1 for survival, which promotes de novo and acquired resistance to standard-of-care therapies. Herein, we survey the history and advancement of small molecule Mcl-1 inhibitors, from novel screening approaches and hit optimization to clinical candidates. The drug discovery efforts spanning academia and industry have afforded five different Mcl-1 inhibitors that are currently being evaluated in phase I clinical trials to treat a variety of hematological malignancies. The most forefront and seminal Mcl-1 inhibitor development programs are summarized from their medicinal chemistry efforts and structure activity relationship studies to their biological efficacy demonstrating utility as anti-cancer agents. This chapter serves as a current state of Mcl-1 inhibitor development and contains a wealth of medicinal chemistry knowledge towards drugging protein–protein interactions.