Smac Mimetics
Smac mimetics are a new class of targeted small molecule drugs for the treatment of solid tumors and hematologic cancers. Smac mimetics specifically induce cancer cell death and inhibit fundamental mechanisms of cancer cell survival and resistance. The unique mechanisms of action of Smac mimetics also enhance the therapeutic activity of a broad range of cancer therapies.
Apoptosis or programmed cell death is a highly controlled biological mechanism by which cells die and is the primary way that cancer cells are destroyed by cancer therapies and the body's immune system. Apoptosis can be activated through two pathways: the extrinsic pathway, mediated by stimulation of cell death receptors binding to cellular microenvironment signals such as tumor necrosis factor alpha (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL); and the intrinsic mitochondrial apoptotic pathway, which is activated by a number of signals such as hypoxia, oxidative stress, chemotherapies and irradiation. Both pathways converge in a common pathway that ultimately leads to caspase activation and apoptosis.
Defective or dysregulated apoptosis is a major cause of cancer development and progression, and plays a significant role in cancer resistance to chemotherapies, radiation and targeted cancer therapies. Inhibitor of Apoptosis Proteins (IAPs) are a family of cellular proteins that regulate apoptosis and cancer cell survival, and represent the last line of defense for cancer against cell death by apoptosis. IAPs are viewed as one of the most prevalent factors responsible for cancer survival, progression and poor prognosis, and are associated with tumor resistance to therapies.
Smac (second mitochondrial-derived activator of caspases) is the endogenous cellular antagonist of IAPs. Smac binds to and inhibits the activity of IAPs by inducing their degradation and eliminating their inhibitory effect on caspases and apoptosis. In cancer, there is an imbalance between IAPs and Smac, resulting in elevated levels of IAPs that protect cancer cells from dying. Smac mimetics are a new class of small molecule drugs designed to mimic the action of Smac and correct the cancer imbalance. By targeting and eliminating IAPs, Smac mimetics re-activate death signals in cancer cells, inhibit resistance mechanisms and induce tumor death by apoptosis.
The activity of Smac mimetics is applicable to all types of solid tumor and hematological cancers.