CCT-137690

The aurora kinases belong to serine/threonine protein kinases family and are also referred to as ''mitotic kinases'' since they have a pivotal role in eukaryotic cell division.Clin. trials of several inhibitors of the Aurora kinase family are currently undergoing development with promising results.Cell toxicity is a major concern while considering the development of Aurora kinase inhibitors for clin. use.Hence, future researches should focus on developing aurora kinase inhibitors that specifically target cancer cells but not the normal cells.However, discovering potential targets associated with aurora kinases that are involved in tumorigenesis can shed light on cancer therapy through combination chemotherapy.

Esophageal adenocarcinoma is of increasing global concern due to increasing incidence, a lack of effective treatments, and poor prognosis. Therapeutic target discovery and clinical trials have been hindered by the heterogeneity of the disease, the lack of "druggable" driver mutations, and the dominance of large-scale genomic rearrangements. We have previously undertaken a comprehensive small-molecule phenotypic screen using the high-content Cell Painting assay to quantify the morphological response to a total of 19,555 small molecules across a panel of genetically distinct human esophageal cell lines to identify new therapeutic targets and small molecules for the treatment of esophageal adenocarcinoma. In this current study, we report for the first time the dose-response validation studies for the 72 screening hits from the target-annotated LOPAC and Prestwick FDA-approved compound libraries and the full list of 51 validated esophageal adenocarcinoma-selective small molecules (71% validation rate). We then focus on the most potent and selective hit molecules, elesclomol, disulfiram, and ammonium pyrrolidinedithiocarbamate. Using a multipronged, multitechnology approach, we uncover a unified mechanism of action and a vulnerability in esophageal adenocarcinoma toward copper-dependent cell death that could be targeted in the future.