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Development of allosteric inhibitors against a molecular target (IKK) induced by cytokines and cigarette smoke

Institution: University of California, San Diego
Investigator(s): Gourisankar Ghosh,
Award Cycle: 2019 (Cycle 29) Grant #: T29IR0262 Award: $921,703
Subject Area: Cancer
Award Type: High Impact Research Project Award

Initial Award Abstract
DNA sequence analysis of lung cancers (LC) revealed that patients with a history of smoking had accumulated a significantly larger number of mutations in a selective number of genes than non-smoking patients. This is consistent with the fact that smokers experience a far greater number of cancer incidences than non-smokers. Not surprisingly, genes that are frequently mutated in LC patients due to cigarette smoke (CS) are involved in cell division and survival. One of the critical genes that is impacted in lung cancer and inflammation is known as IkappaB kinase (IKK). Activation of IKK is essential for the generation of active NF-kB, an important protein that regulates the expression of a large number of cell division, survival and inflammatory genes. Uncontrolled and untimely activity of IKK is seen in different cancer cells including lung cancer. Many of the genes mutated in LC render IKK constitutively active. In addition, CS directly activates IKK by an unknown mechanism. It was thought that reduction of IKK activity using small molecule inhibitors could be a strategy to combat cancer and other diseases such as chronic obstructive pulmonary disease (COPD). Although many inhibitors were developed, none turned out to be a drug. The lack of knowledge of how IKK is activated might be one of the reasons for this failure. This proposal plans to investigate the IKK activation mechanism at a molecular level and then develop inhibitors that will block IKK activation but not its global catalytic activity.

We hypothesized a possible activation mechanism which is supported by preliminary experiments. We have further performed an initial screen of a small molecule library and identified lead IKK inhibitors. We identified the inhibitor binding site in IKK and showed that these new inhibitors are different from ones previously reported. This proposal has devised experiments to elucidate the detailed mechanism of IKK activation by CS and by molecules released normally by cells. At the same time, other experiments have been planned to improve the quality of the inhibitors. To test the effectiveness of these current and new inhibitors, we will use lung cancer cells generated from patients with a history of smoking. In the future, we hope to use one or more of the inhibitors developed in this study to be tested in animal models of LC.