Orally available Phase I candidate is designed to block inhibitors of apoptosis.
Deboiopharm and cancer drugs firm Ascenta Therapeutics inked an exclusive license agreement for development and commercialization of the latter’s Phase I-stage candidate AT-406, an orally available small molecule that is designed to neutralize major inhibitors of apoptosis (known as “inhibitors of apoptosis proteins” [IAPs]). Debiopharm will designate the molecule Debio 1143, and says the potential exists to combine the candidate with other pro-apoptotic agents to boost cancer cell death.
Ascenta’s core focus is on the development of drugs that re-establish apoptosis pathways in abnormal cancer cells. AT-406 is designed to block the activity of a number of IAPs including XIAP, c-IAP1, c-IAP2, and ML-IAP. The firms says the drug is believed to act by mimicking 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.
T-406 has demonstrated single-agent antitumor activity in multiple xenograft models of human cancers, and also works synergistically with conventional chemotherapeutic and targeted agents, Ascenta notes. The drug is currently undergoing clinical trials in the U.S. in patients with a range of solid tumors and lymphomas. The firm is in addition collaborating with The Leukemia and Lymphoma Society to develop AT-406 against hematologic malignancies such as acute myeloid leukemia (AML), and also has an ongoing partnership with Ascentage Pharma manufacturing and clinical development of AT-406 for China.
The firm has currently has two additional small molecule programs against distinct apoptosis targets: AT-101 is a Phase II-stage oral pan-Bcl2 inhibitor, an HDM2 inhibitor is in preclinical development in partnership with Sanofi-Aventis. AT-101 is designed to inhibit multiple Bcl-2 family proteins (including Bcl-2, Bcl-xL, Bcl-w, and Mcl-1), which directly induces apoptosis by acting as a BH3 mimetic, and indirectly operates as a p53-independent upregulator of Noxa and Puma. The firm says that by blocking the binding of Bcl-2 proteins with proapoptotic proteins and upregulating specific proapoptotic factors AT-101 essentially lowers the threshold for cancer cells to undergo apoptosis in various tumor types.
Clinical trials with AT-101 are ongoing in the U.S. and Europe. Phase I and Phase II trials evaluating AT-101 as single-agent therapy have already demonstrated cytoreductive activity in several cancers, including chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), and prostate cancer. Phase II trials evaluating AT-101 in combination with chemotherapy and/or radiotherapy have also been carried out in a number of cancers including hormone-refractory prostate cancer, non-small cell lung cancer, B-cell malignancies, small cell lung cancer, glioma, and esophageal cancer. Ascentage Pharma has rights to AT-101 in all regions outside the U.S., Canada, and Europe.
