Therapeutics
SMAC MIMETICS
a new class of targeted agents that activate apoptotic cell death and block pro-survival signalling in cancer cells
Smac mimetics are a new class of targeted drugs being developed for the treatment of solid tumours and hematologic cancers. Smac mimetics specifically induce apoptotic cancer cell death and block pro-survival signalling in cancer cells. This article provides an overview of the biology of Smac, an endogenous pro-apoptotic molecule, and the development of Smac mimetics as a novel therapeutic approach to treat cancer.
R
ecent advances in the field of cancer biolo- gy have helped to address the challenges of existing cancer therapies and pave the way for new classes of therapeutic agents that target cellular pathways involved in the formation, pro- gression and death of tumour cells. Numerous can- cer therapies depend on the tumour cells’ ability to undergo apoptosis (programmed cell death). However, tumour cells typically develop a series of mutations that can lead to uncontrolled prolifera- tion and also enable them to evade apoptotic death. Dysregulation of the apoptotic pathways is a major contributor to cancer development and progression, and plays a significant role in cancer resistance to chemotherapies, targeted therapies and radiation. Even if tumours initially respond to these therapies, they often acquire resistance dur- ing the course of treatment. Tumour cells can resist apoptosis by increasing expression of proteins that block pro-apoptotic pathways. Overcoming the fundamental mechanisms of cancer resistance and survival, and activating cancer cell death through apoptosis is a focus of current trends in cancer research and drug development. One novel thera- peutic approach is the development of small mole- cule drugs that mimic Smac (second mitochondria-
Drug Discovery World Fall 2011
derived activator of caspase), a pro-apoptotic mitochondrial protein that is an endogenous inhibitor of a family of cellular proteins called the Inhibitor of Apoptosis Proteins (IAPs). IAPs regu- late apoptosis and cancer cell survival and repre- sent the last line of defence for cancer against cell death by apoptosis. Clinically, IAPs are a key fac- tor in cancer survival, progression and poor prog- nosis and are associated with tumour resistance to therapies, and as such, are recognised as important therapeutic targets to selectively induce apoptosis in tumour cells. The goal of Smac mimetics (also called IAP antagonists) is to suppress the IAPs, re- establishing the apoptotic pathways and inducing cancer cell death. The unique action of Smac mimetics can also enhance the therapeutic activity of many existing cancer therapies.
This article will provide an overview of the biol- ogy of IAPs, its natural inhibitor Smac and the cur- rent status of the clinical development of Smac mimetics, which target IAPs in cancer.
Inhibitor of Apoptosis Protein (IAP) Family
The Inhibitor of Apoptosis Proteins (IAPs) are important regulators of cell death and survival.
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By Dr Mark A. McKinlay
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