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 AT-406

Description of AT-406 : AT-406 (formerly known as SM-406) is an orally bioavailable inhibitor of IAP (Inhibitor of Apoptosis Protein) with potential apoptotic inducing and antineoplastic activity. AT-406 selectively inhibits the biological activity of IAP proteins, including X chromosome-linked IAP (XIAP), the cellular IAPs 1 (c-IAP1) and 2 (c-IAP2) and melanoma inhibitor of apoptosis protein (ML-IAP). This may restore and promote the induction of apoptosis through apoptotic signaling pathways. AT-406 may work synergistically with cytotoxic drugs to overcome tumor cell resistance to apoptosis. IAPs are overexpressed by many cancer cell types, suppressing apoptosis by binding and inhibiting active caspases-3, -7 and -9 via their BIR (baculoviral lAP repeat) domains. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:   Ascenta Therapeutics, Inc.

AT-406, currently being developed by   Ascenta Therapeutics, has demonstrated strong single-agent antitumor activity in multiple xenograft models of human cancer, including breast cancer, pancreatic cancer, prostate cancer, and lung cancer. AT-406 has also been shown to work synergistically with conventional chemotherapeutic and targeted agents (such as TRAIL and tyrosine kinase inhibitors) in preclinical tumor models. (source: http://www.ascenta.com/development/index.php).

Preclinical evaluation of AT-406: According to news release by Ascenta Therapeutics, The preclinical research of AT-406 has demonstrated that AT-406 showed strong single-agent antitumor activity in multiple xenograft models of human cancer, including breast cancer, pancreatic cancer, prostate cancer, and lung cancer. AT-406 has also been shown to work synergistically with conventional chemotherapeutic and targeted agents (such as tyrosine kinase inhibitors) in preclinical tumor models.

Recent result showed that AT-406 has significant single agent activity in 60% of human ovarian cancer cell lines examined in vitro and inhibits ovarian cancer progression in vivo and that 3 out of 5 carboplatin-resistant cell lines are sensitive to AT-406, highlighting the therapeutic potential of AT-406 for patients with inherent or acquired platinum resistance. Additionally, our in vivo studies show that AT-406 enhances the carboplatin-induced ovarian cancer cell death and increases survival of the experimental mice, suggesting that AT-406 sensitizes the response of these cells to carboplatin. Mechanistically, we demonstrate that AT-406 induced apoptosis is correlated with its ability to down-regulate XIAP whereas AT-406 induces cIAP1 degradation in both AT-406 sensitive and resistance cell lines. Together, these results demonstrate, for the first time, the anti-ovarian cancer efficacy of AT-406 as a single agent and in the combination with carboplatin, suggesting that AT-406 has potential as a novel therapy for ovarian cancer patients, especially for patients exhibiting resistance to the platinum-based therapies. (source: Cancer Biol Ther. 2012 Jul 1;13(9). [Epub ahead of print]).

1: Brunckhorst MK, Lerner D, Wang S, Yu Q. AT-406, an orally active antagonist of multiple inhibitor of apoptosis proteins, inhibits progression of human ovarian cancer. Cancer Biol Ther. 2012 Jul 1;13(9). [Epub ahead of print] PubMed PMID: 22669575.

2. Cai Q, Sun H, Peng Y, Lu J, Nikolovska-Coleska Z, McEachern D, Liu L, Qiu S, Yang CY, Miller R, Yi H, Zhang T, Sun D, Kang S, Guo M, Leopold L, Yang D, Wang S. A potent and orally active antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in clinical development for cancer treatment. J Med Chem. 2011 Apr 28;54(8):2714-26.

3. Targeting cancer stem cells By Buchsbaum, Donald J.; LoBuglio, Albert F.; Zhou, Tong From PCT Int. Appl. (2011), WO 2011116344 A2 20110922.

4. Potent Bivalent Smac Mimetics: Effect of the Linker on Binding to Inhibitor of Apoptosis Proteins (IAPs) and Anticancer Activity By Sun, Haiying; Liu, Liu; Lu, Jianfeng; Bai, Longchuan; Li, Xiaoqin; Nikolovska-Coleska, Zaneta; McEachern, Donna; Yang, Chao-Yie; Qiu, Su; Yi, Han; et al From Journal of Medicinal Chemistry (2011), 54(9), 3306-3318.

5. Preparation of diazo bicyclic conformationally constrained Smac peptide mimetics as inhibitors of IAP proteins and inducers of apoptosis By Wang, Shaomeng; Peng, Yuefeng; Sun, Haiying; Cai, Qian; Nikolovska-Coleska, Zaneta; Lu, Jianfeng; Qiu, Su From PCT Int. Appl. (2008), WO 2008128171 A2 20081023.