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

Abstract

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.

Keywords:

• Gli
• hedgehog signaling
• mesothelioma
• non-small cell lung cancer
• pyrazoline

Declaration of interest

The author received funding from the American Cancer Society (RSG-13-131-01) and the National Institutes of Health (1R01CA190617-01) to develop Hh pathway inhibitors based on the vitamin D3 and itranconazole scaffolds, respectively. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.