Candidate Cancer Drug Blocks Proteins That Inhibit Apoptosis

An orally deliverable drug that blocks the activity of proteins that prevent cells from entering apoptosis has been found to shrink tumors significantly in animals with only minimal side effects.

The drug, AT-406, mimics the action of the protein Smac (second mitochondria-derived activator of caspases), a mitochondrial protein that enables apoptosis, possibly by neutralizing one or more members of the IAP family of apoptosis inhibitory proteins. The inhibitors of apoptosis (IAP) are a family of functionally- and structurally-related proteins, which serve as endogenous inhibitors of programmed cell death. The human IAP family consists of at least six members, and IAP homologs have been identified in numerous organisms.

Smac has been shown to exit mitochondria and enter the cytosol during apoptosis triggered by UV- or gamma-irradiation. In the cytosol Smac moderates the caspase inhibition of IAPs.

Investigators at the University of Michigan (Ann Arbor, USA) first synthesized AT-406 in 2006. Since then they have demonstrated that the drug blocked IAP activity in a variety of cell free systems. In the current study, which was published in the March 28, 2011, issue of the Journal of Medicinal Chemistry, they examined the effect of AT-406 on human cancer cells growing in culture and on tumors in animal models.

They found that the drug inhibited cancer cell growth in various human cancer cell lines. It had good oral bioavailability in mice, rats, nonhuman primates, and dogs, was highly effective in induction of apoptosis in xenograft tumors, and was capable of complete inhibition of tumor growth.

"Removing key apoptosis blockades in tumor cells is a completely new cancer therapeutic approach and could have benefit for the treatment of many types of human tumors,” said senior author Dr. Shaomeng Wang, professor of medicine at the University of Michigan.

Patent applications covering the drug are exclusively licensed to Ascenta Therapeutics (Malvern, PA, USA), a privately held, clinical stage biopharmaceutical company cofounded by Dr. Wang. After extensive testing, in 2010 Ascenta began the first clinical trial of AT-406 as a potential cancer treatment.

Related Links:
University of Michigan
Ascenta Therapeutics