Ascenta's Pipeline
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Our approach to oncology drug development represents a highly promising therapeutic strategy for anticancer drug design. Multicellular organisms use apoptosis, or programmed cell death, to eliminate abnormal or unwanted cells. Cancer cells typically have a variety of alterations leading to deregulation of signal transduction and apoptosis pathways. All cancer cells fail to execute an apoptotic program - a breakdown in cellular apoptosis regulatory machinery is a hallmark of cancer - allowing them to grow uncontrollably. Most of the current cancer therapies, including chemotherapeutic agents, radiation, and immunotherapy, work by indirectly inducing apoptosis in cancer cells. Some cancer cells are resistant to these types of therapeutic agents because the normal apoptotic pathways are defective. Accordingly, new, target-specific anticancer therapies, such as AT-101, directly target apoptotic proteins and overcome cancer cell resistance to apoptosis. Our pipeline includes several anticancer therapies that target different parts of the apoptotic pathway.
Read Article: Inhibitors of the Bcl-2 Family of Proteins – AT-101
Read Article: Inhibiting the p53-MDM2 Interaction – AT-219
Read Article: IAP Inhibitors or Smac Mimetics - AT-406
Inhibitors of the Bcl-2 Family of Proteins
The Bcl-2 family of proteins is pivotal to regulating apoptosis. These proteins share conserved regions known as the Bcl-2 homology (BH) regions (BH1, BH2, BH3, BH4), which control the ability of the Bcl-2 proteins to bind to each other and regulatory proteins. Defective regulation of apoptosis is central to cancer pathogenesis and progression, and has been associated with resistance to standard therapy.
The antiapoptotic proteins, Bcl-2 and Bcl-xL, bind to the BH3 domains of proapoptotic family members, and prevent them from stimulating apoptosis. Other proapoptotic Bcl-2 family proteins (eg, Bad, Bid, Bim), the "BH3-only" proteins, activate Bax and Bak that sequester Bcl-2. Numerous peptide and non-peptide BH3 mimetics have been shown in laboratory studies to inhibit the binding of Bcl-2 or Bcl-xL to proapoptotic BH3 family members.
Antiapoptotic Bcl-2 family proteins are overexpressed in many cancers, and have been proposed as therapeutic targets in non-Hodgkin lymphoma (Bcl-2), myeloma (Mcl-1), chronic lymphocytic leukemia (Bcl-2 and Mcl-1), prostate cancer (Bcl-xL and Bcl-2), melanoma (Bcl-2), and other cancers. New drugs that inhibit the function of antiapoptotic Bcl-2 family proteins may be promising cancer medicines, as single agents or in combination with other agents or modalities. However, no such drugs have yet been approved in the United States.
AT-101, our lead product, is an oral pan-Bcl-2 inhibitor (including Bcl-2, Bcl-xL, Bcl-w, and Mcl-1 inhibition). In phase I and single-agent phase II trials, AT-101 has demonstrated single-agent cytoreductive activity in chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), and prostate cancer. Phase II combination trials are ongoing in 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], +/- chemoradiotherapy [XRT]) and in esophageal cancer (with docetaxel, 5-fluorouracil and XRT). Recently, 2 double-blinded, randomized, controlled trials of the docetaxel + AT-101 combination were opened in hormone-refractory prostate cancer and non-small cell lung cancer, both indications in which docetaxel is approved as a single agent.
Inhibiting the p53-MDM2 Interaction
Another potential drug target in the apoptotic pathway is the proapoptotic p53 tumor suppressor protein, which plays a central role in controlling cell cycle progression and apoptosis. Mutations or deletions of the TP53 gene are found in approximately 50% of human tumors. In cells with wild-type p53, the MDM2 (murine double minute 2) protein, and its human homologue HDM2, binds to p53 in cancer cells and inhibits its activity. Inhibition of the interaction between MDM2 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.
AT-219 is an oral HDM2 inhibitor . AT-219 is a potent small molecule that restores p53 function in cancer cells with wild-type (unmutated) p53.. It is also in late-stage preclinical development. The next key milestones will be completion of toxicology studies, and filing of an investigational new drug (IND) application, with the US Food and Drug Administration (FDA).
IAP Inhibitors or Smac Mimetics
Inhibitors of apoptosis proteins (IAPs) are proteins that interfere with programmed cell death. IAPs suppress apoptosis by binding to and inhibiting the apoptosis initiator, caspase 9, as well as other caspases in the apoptosis cascade. Smac (second mitochondria-derived activator of caspases) binds to and inhibits IAP proteins (eg, XIAP, cIAP1 & 2 and ML-IAP), which allows cells to undergo apoptosis. IAPs represent new and highly promising molecular targets for anticancer drug design. IAPs are overexpressed in a broad range of tumors, including common cancers such as colorectal, breast, lung, and prostate cancers.
AT-406 is an oral IAP inhibitor that works by mimicking Smac. It is in late-stage preclinical development and has demonstrated strong single-agent antitumor activity in multiple xenograft models of human cancer. AT-406 also works synergistically with conventional chemotherapeutics and with targeted agents in preclinical tumor models. The next key milestones will be completing toxicology studies and filing the IND application with the FDA.