Ascenta Therapeutics Announces Results Of Preclinical Evaluation Of AT-406 In Multiple Cancer Models

Main Category: Cancer / Oncology
Also Included In: Clinical Trials / Drug Trials;  Conferences;  Pharma Industry / Biotech Industry
Article Date: 22 Apr 2009 - 3:00 PDT

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Ascenta Therapeutics announced that the results of preclinical studies of its orally-active, small molecule, pro-apoptotic agent, AT-406, have been presented at the 100th Annual Meeting of the American Association for Cancer Research (AACR), in Denver, Colorado (Abstract # 1917).

The studies demonstrated that AT-406 was active as a single agent in vitro in a number of cell lines, including breast cancer, lung cancer, pancreatic cancer, prostate cancer, and bladder cancer, and in several mouse xenograft cancer models. AT-406 also showed synergistic or additive effects when used together with tyrosine kinase inhibitors or chemotherapy in vitro in those cell lines.

"AT-406 is the second agent in our development pipeline to demonstrate broad anti-cancer activity in pre-clinical models, including synergy with other agents, by targeting a specific apoptotic pathway," said Mel Sorensen, MD, CEO of Ascenta Therapeutics. "On the basis of these encouraging data, we plan to submit an Investigational New Drug (IND) application to the U.S. Food and Drug Administration to allow us to begin human clinical trials with AT-406 later this year."

About AT-406

AT-406 is an orally-active, small molecule drug designed to promote programmed cell death (apoptosis) in tumor cells by blocking the activity of at least three "inhibitors of apoptosis proteins" or IAPs (including XIAP, c-IAP1, and c-IAP2) 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 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, AT-406 induces rapid degradation of cIAP-1/2 proteins and promotes apoptosis through activation of caspase-8 and the death-receptor complex.

AT-406 is in late-stage preclinical development and 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 tyrosine kinase inhibitors) in preclinical tumor models.

Other Research Including AT-101

Ascenta Therapeutics also announced that researchers from the University of Pennsylvania presented results at AACR from an independent laboratory study examining the role of Bcl-2 homology (BH) family proteins in the development of chemotherapy resistance in neuroblastoma (Abstract # 3269). Using human-derived neuroblastoma cell lines, these investigators demonstrated differential resistance patterns to inhibitors of the Bcl-2 family proteins based on the relative BH proteins expressed (specifically, Mcl-1 or Bcl-2). They showed that Ascenta's small molecule pan-Bcl-2 inhibitor, AT-101, had preferential inhibition in Mcl-1 predominant lines. They concluded that compounds with activity against Mcl-1 may be useful in the treatment of high-risk neuroblastoma and warrant further study in human clinical trials.

About Ascenta Therapeutics

Ascenta Therapeutics, Inc. is a privately-held, clinical-stage biopharmaceutical company that discovers and develops new medicines for the treatment of cancer. The company is headquartered in Malvern, Pennsylvania, and has a preclinical research facility in Shanghai, China. Its technology, licensed from both the National Institutes of Health and the laboratory of Dr. Shaomeng Wang at the University of Michigan, is focused on discovering molecules that restore the natural potential for cancer cells to undergo cell death (apoptosis). Ascenta's lead agent, AT-101, is an orally-active small molecule pan Bcl-2 inhibitor (Bcl-2, Bcl-xL, and Mcl-1) currently in Phase 2 clinical trials in castrate resistant prostate cancer. The Company's preclinical pipeline includes the oral multi-IAP antagonist AT-406, and an HDM2-p53 inhibitor program.

Source: Ascenta Therapeutics, Inc

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