Key result
Srx-null mice showed resistance to urethane-induced lung cancer, and virtual screening identified ISO1 as an inhibitor of the Srx-Prx interaction with a KD of 42 nM.
The Srx-Prx axis plays a critical role in lung carcinogenesis, and ISO1 is a potential small-molecule inhibitor for future therapeutic development.
Positions Srx-Prx as a lung carcinogenesis target in mice; leaves open whether ISO1 advances to clinical testing.
Lung cancer is a leading cause of cancer-related mortality irrespective of gender. The Sulfiredoxin (Srx) and Peroxiredoxin (Prx) are a group of thiol-based antioxidant proteins that plays an essential role in non-small cell lung cancer. Understanding the molecular characteristics of the Srx-Prx interaction may help design the strategies for future development of therapeutic tools. Based on existing literature and preliminary data from our lab, we hypothesized that the Srx plays a critical role in lung carcinogenesis and targeting the Srx-Prx axis or Srx alone may facilitate future development of targeted therapeutics for prevention and treatment of lung cancer. First, we demonstrated the oncogenic role of Srx in urethane-induced lung carcinogenesis in genetically modified FVB mice. The Srx-null mice showed resistance to urethane-induced lung cancer. Second, we demonstrated the Srx and Prx sites important for Srx-Prx interaction. The orientation of this arm is demonstrated to cause some steric hindrance for the Srx-Prx interaction as it substantially reduces the rate of association between Srx and Prx. Finally, we carried out virtual screening to identify molecules that can successfully target Srx-Prx interaction. Multiple in-silico filters were used to minimize the number of chemicals to be tested. We identified ISO1 as an inhibitor of the Srx-Prx interaction. KD value for Srx-ISO1 interaction is calculated to be 42 nM. Together, these data helps to identify an inhibitor (ISO1) of the Srx-Prx interaction that can be further pursued to be developed as a chemotherapeutic tool.
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Murli Mishra (2016) studied Lung cancer. Srx-null mutation and ISO1 inhibitor vs. Wild-type mice / Control was evaluated on Urethane-induced lung carcinogenesis and Srx-Prx interaction inhibition (KD 42 nM). Srx-null mice showed resistance to urethane-induced lung cancer, and virtual screening identified ISO1 as an inhibitor of the Srx-Prx interaction with a KD of 42 nM.
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