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Multiparametric High-Content Cell Painting Identifies Copper Ionophores as Selective Modulators of Esophageal Cancer Phenotypes.

ABSTRACT: 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.

SUBMITTER: Hughes RE

PROVIDER: S-EPMC9295120 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Multiparametric High-Content Cell Painting Identifies Copper Ionophores as Selective Modulators of Esophageal Cancer Phenotypes.

Hughes Rebecca E RE Elliott Richard J R RJR Li Xiaodun X Munro Alison F AF Makda Ashraff A Carter Roderick N RN Morton Nicholas M NM Fujihara Kenji K Clemons Nicholas J NJ Fitzgerald Rebecca R O'Neill J Robert JR Hupp Ted T Carragher Neil O NO

ACS chemical biology 20220613 7

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 respo ...[more]

PMID: 35696676

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Project description:Manganese(III) complexes of three fluorophilic salen derivatives were used to prepare ion-selective electrodes (ISEs) with ionophore-doped fluorous sensing membranes. Because of their extremely low polarity and polarizability, fluorous media are not only chemically very inert but also solvate potentially interfering ions poorly, resulting in a much improved discrimination of such ions. Indeed, the new ISEs exhibited selectivities for CO(3)(2-) that exceed those of previously reported ISEs based on nonfluorous membranes by several orders of magnitude. In particular, the interference from chloride and salicylate was reduced by 2 and 6 orders of magnitude, respectively. To achieve this, the selectivities of these ISEs were fine-tuned by addition of noncoordinating hydrophobic ions (i.e., ionic sites) into the sensing membranes. Stability constants of the anion-ionophore complexes were determined from the dependence of the potentiometric selectivities on the charge sign of the ionic sites and the molar ratio of ionic sites and the ionophore. For this purpose, a previously introduced fluorophilic tetraphenylborate and a novel fluorophilic cation with a bis(triphenylphosphoranylidene)ammonium group, (R(f6)(CH(2))(3))(3)PN(+)P(R(f6)(CH(2))(3))(3), were utilized (where R(f6) is C(6)F(13)). The optimum CO(3)(2-) selectivities were found for sensing membranes composed of anionic sites and ionophore in a 1:4 molar ratio, which results in the formation of 2:1 complexes with CO(3)(2-) with stability constants up to 4.1 × 10(15). As predicted by established theory, the site-to-ionophore ratios that provide optimum potentiometric selectivity depend on the stoichiometries of the complexes of both the primary and the interfering ions. However, the ionophores used in this study give examples of charges and stoichiometries previously neither explicitly predicted by theory nor shown by experiment. The exceptional selectivity of fluorous membranes doped with these carbonate ionophores suggests their use not only for potentiometric sensing but also for other types of sensors, such as the selective separation of carbonate from other anions and the sequestration of carbon dioxide.

Dataset Information

Multiparametric High-Content Cell Painting Identifies Copper Ionophores as Selective Modulators of Esophageal Cancer Phenotypes.

Publications

Multiparametric High-Content Cell Painting Identifies Copper Ionophores as Selective Modulators of Esophageal Cancer Phenotypes.

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