Reata’s Antioxidant Inflammation Modulator (AIM) molecules are potent inhibitors of the NF-κB and JAK/STAT signaling pathways, which play critical roles in promoting inflammation, carcinogenesis, and tumor growth. Inhibition of these transcription factors is achieved in part by activation of the antioxidant transcription factor Nrf2, which induces the phase 2 antioxidant/detoxification response and reduces cellular levels of ROS. In addition, AIMs directly inhibit activation of NF-κB by binding to IKKβ, the kinase that regulates NF-κB activation. They also act directly on targets in the JAK/STAT pathway, and have been shown to inhibit activation of STAT3 and STAT5 in cancer cells.
All of these targets are part of a highly coordinated network of proteins designed by evolution to monitor and respond to changes in the cell’s oxidative status. Under normal circumstances, production of reactive oxygen species (ROS) such as hydrogen peroxide and reactive nitrogen species (RNS) such as nitric oxide is tightly regulated by this network. Under special circumstances, such as the initiation of an inflammatory response to infection, large amounts of ROS/RNS may be produced by specific cells for limited periods. This pro-inflammatory state is also characterized by the production of a variety of inflammatory signaling proteins (cytokines), including TNF-α and IL-6. This acute inflammatory response is ordinarily followed by a process of orchestrated resolution, in which ROS/RNS production and cytokine signaling return to a normal state. In pathological states such as cancer, chronic inflammation, and autoimmune disease, normal resolution does not occur and ROS/RNS levels as well as cytokine levels remain elevated. Recent research has identified a group of cyclopentenone prostaglandins that play a critical role in the natural, orchestrated resolution of inflammation. Research by Reata scientists and their collaborators has demonstrated that the pharmacology of AIMs closely mimics that of cyclopentenone prostaglandins. Consequently, AIMs have demonstrated potent antioxidant, anti-inflammatory, and anticancer effects in many different animal models of disease. Most importantly, human clinical studies have demonstrated that RTA 402, Reata’s most advanced AIM, is extremely well tolerated, has significant anticancer effects, inhibits NF-kB and STAT3 activity in tumor tissue, and reduces circulating levels of major inflammatory cytokines.
NF-kB, Nrf2, and JAK/STAT signaling are separately recognized as important therapeutic targets for treating and preventing a wide variety of diseases that involve oxidative stress and inflammation, including cancer, cardiovascular and renal diseases, autoimmune diseases, transplants, major respiratory diseases, and neurodegenerative diseases. Accordingly, a number of drug discovery programs have focused on one of these targets or on one of their downstream effects. By modulating all of these targets in the same fashion as the endogenous molecules that resolve oxidative stress and inflammation, AIMs overcome the problems posed by the complexity and redundancy of the relevant signaling pathways, and offer a unique profile of efficacy. |
