ATN-224

ATN-224 is an orally available small molecule that inhibits multiple kinase signaling pathways important for tumor growth, angiogenesis, and metastasis. ATN-224 has been demonstrated to inhibit:

• VEGF and FGF-2 signaling in endothelial cells,
• IGF-1, EGF, and integrin signaling in tumor cells,
• PDGF signaling in pericytes, and
  
• NF-κB, which is thought to be important to tumor cell survival and resistance to chemotherapy.

Since these pathways have been implicated in tumor progression in many different tumor types, ATN-224 has the potential to be effective against numerous cancer indications. In addition, ATN-224 can affect multiple cell types within a tumor, possibly exerting both antitumor and antiangiogenic effects in a broader way than other signaling inhibitors.

ATN-224 disrupts signaling pathways through inhibition of copper-zinc superoxide dismutase, by removing copper from this enzyme. The inhibition of SOD1 causes a decrease in intra-cellular H₂O₂ levels, which in turn leads to increased activity of phosphatases, a class of enzymes that turn off kinase signaling. Kinases such as EGFR, VEGFR, PDGFR, Abl, and Raf have already been validated clinically. Drugs that target some of them have been approved for the treatment of cancer and others are in development. By preventing the inhibition of phosphatases that turn off kinase signaling, ATN-224 is able to inhibit many of these kinases simultaneously and may not be subject to the same problems of resistance or redundancy that occur when the kinases are targeted selectively and directly.

ATN-224 has been evaluated in two phase I trials; one involving patients with solid tumors in collaboration with Cancer Research UK in the United Kingdom and the second involving patients with advanced hematologic (blood) malignancies at multiple centers in the United States.  The phase II program has begun in the United States and is pending regulatory approval in the United Kingdom. Click here for a list of active trials.