Targeting GLI proteins in human cancer by small molecules (WO2014116651 A1): a patent evaluation

The invention reviewed in this patent evaluation is the synthesis and application of small molecule inhibitors of Gli transcriptional activity as potential anticancer agents. The oncogenic nature of Gli proteins has been traditionally associated with the hedgehog (Hh) signaling pathway; however, the recent identification of aberrant Gli activation unrelated to Hh signaling has prompted drug discovery efforts directly targeting Gli proteins. The central core of the compounds described in this patent (WO2014116651 A1) is structurally analogous to the pyrazoline scaffold previously disclosed by these inventors. Data describing the inhibitory activity of these compounds against the Hh pathway in vitro and in Hh-dependent in vivo models of human cancer are not provided. For this patent disclosure, the inventors primarily focus on the anticancer properties of their compounds in lung and lung-related malignancies. The compounds are moderately active in these models, but they do not exhibit the overall preclinical profile generally required for advancement into clinical trials.