- Introduction and Scientific Approach
- Clinical Portfolio
- AT-101: Bcl-2 Inhibitor
- AT-406: IAP Inhibitor
- HDM2 Inhibitor
Apoptosis, or “programmed cell death,” is a precisely regulated, complex process through which normal cells in the body die after a specified life span, ensuring that defective, damaged or redundant cells are eliminated.
Multicellular organisms use apoptosis, or programmed cell death, to eliminate abnormal or unwanted cells. As a result of accumulated mutations, all cancer cells fail to execute an apoptotic program, allowing them to live indefinitely and grow uncontrollably. In fact, the breakdown of the cellular apoptosis regulatory machinery is a hallmark of cancer. Most current cancer therapies, including chemotherapeutic agents, radiation, and immunotherapy, work by inducing apoptosis in cancer cells. However, because the normal apoptotic pathways are defective, many cancer cells are resistant or develop resistance to these agents. A promising new direction for drug development involves targeting apoptotic proteins directly to induce cell death and/or reduce resistance to other treatments.
We and our partners are developing a portfolio of small-molecule agents that restore a tumor cell’s apoptotic program by inhibiting or interacting with a number of key proteins (or their inhibitors) in this cascade. These include the Bcl-2 family of proteins, the inhibitors of apoptosis proteins (IAPs), and the p53 tumor suppressor protein.
AT-101 is a member of an emerging class of cancer drugs that stimulates apoptosis in cancer cells by inhibiting multiple Bcl-2 family proteins. AT-101 is an orally-active, pan-Bcl-2 inhibitor (including Bcl-2, Bcl-xL, Bcl-w, and Mcl-1 inhibition), that has been shown to directly induce apoptosis by operating as a BH3 mimetic and indirectly as a p53-independent upregulator of Noxa and Puma. By blocking the binding of Bcl-2 family members with proapoptotic proteins and upregulating specific proapoptotic factors, AT-101 lowers the threshold for cancer cells to undergo apoptosis in various tumor types.
In Phase I and Phase II trials, AT-101 has demonstrated single-agent cytoreductive activity in several cancers, including chronic lymphocytic leukemia (CLL), non-Hodgkins lymphoma (NHL), and prostate cancer. Phase II combination trials were conducted in several cancers, including hormone-refractory prostate cancer and non-small cell lung cancer (with Taxotere® [docetaxel]), B-cell malignancies (with Rituxan® [rituximab]), small cell lung cancer (with Hycamtin® [topotecan]), glioma (with Temodar® [temozolomide], +/- radiotherapy) and esophageal cancer (with docetaxel, 5-fluorouracil and radiotherapy).
Clinical trials are ongoing in the US and Europe and Ascenta is collaborating with Ascentage Pharma Group Corporation (located in Hong Kong and Shanghai) for the clinical development of AT-101 in China.
AT-406 is an orally-active, small molecule drug designed to promote programmed cell death (apoptosis) in tumor cells by blocking the activity of "inhibitors of apoptosis proteins" or IAPs (including XIAP, c-IAP1, c-IAP2, and ML-IAP) to create conditions in which apoptosis can proceed. As such, AT-406 is considered a multi-IAP antagonist. IAPs are key components of the complex cascade of protein signaling that activates enzymes called caspases to initiate the breakdown of the cancer cell. AT-406 is thought to mimic the activity of Smac (second mitochondria-derived activator of caspases) by binding to XIAP and preventing it from inhibiting caspase activation. Upon binding to cIAP1 and cIAP2, AT-406 induces rapid degradation of these proteins and promotes apoptosis through activation of the death-receptor complex and caspase 8. AT-406 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. Ascenta is conducting clinical trials of AT-406 in the US in patients with a variety of solid tumors and lymphomas. AT-406 was licensed to Debiopharm S. A. in August 2011.
Ascenta's third program involves inhibition of HDM2 (Human double Minute 2), a protein that regulates the activity of another important component of the apoptotic pathway, the p53 tumor suppressor protein. Mutations or deletions of the p53 gene are found in approximately 50% of human tumors. In cells with wild-type p53, the HDM2 protein binds to p53 in cancer cells and inhibits its activity. Inhibition of the interaction between HDM2 and p53 stimulates p53 activity and subsequently apoptosis. A new and promising approach for the development of anticancer agents is the inhibition of the HDM2-p53 interaction using non-peptide small-molecule inhibitors. In June 2010, Ascenta entered into a global R&D Collaboration with Sanofi for compounds against this HDM2-p53 target.