TY - JOUR
T1 - Multiparametric High-Content Cell Painting Identifies Copper Ionophores as Selective Modulators of Esophageal Cancer Phenotypes
AU - Hughes, Rebecca E.
AU - Elliott, Richard J. R.
AU - Li, Xiaodun
AU - Munro, Alison F.
AU - Makda, Ashraff
AU - Carter, Roderick N.
AU - Morton, Nicholas M.
AU - Fujihara, Kenji
AU - Clemons, Nicholas J.
AU - Fitzgerald, Rebecca
AU - O’neill, J. Robert
AU - Hupp, Ted
AU - Carragher, Neil O.
N1 - Funding Information:
The authors declare the following competing financial interest(s): RCF is named on patents related to Cytosponge and associated assays which is a diagnostic test for oesophageal cancer and these have been licensed by the MRC to Covidien (now Medtronic). RCF is a co-founder and shareholder of Cyted Ltd a diagnostics company. RCF has given paid webinars for Bristol Myers Squibb and received grant funding from Roche and Astra Zeneca. Acknowledgments
Funding Information:
This study was supported by an MRC Institute of Genetics and Molecular Medicine Ph.D. studentship Award to R.E.H., the Anne Forrest Fund for Esophageal Cancer Research, and a CRUK Small-Molecule Drug Discovery Project Award to N.O.C. (C42454/A24892). R.N.C. and N.M.M. were supported by a Wellcome Trust New Investigator Award (100981/Z/13/Z) to N.M.M. N.J.C. was awarded a National Health and Medical Research Council (NHMRC) Project Grant (APP1120293) and is supported by a Fellowship (MCRF16002) from the Department of Health and Human Services acting through the Victorian Cancer Agency. K.F. is supported by an Australian Research Training Program (RTP) Scholarship. The laboratory of RCF is funded by a Programme Grant from the Medical Research Council (MR/W014122/1, G111260).
Publisher Copyright:
© 2022 The Authors. Published by American Chemical Society.
PY - 2022/6/13
Y1 - 2022/6/13
N2 - 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
AB - 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
U2 - 10.1021/acschembio.2c00301
DO - 10.1021/acschembio.2c00301
M3 - Article
JO - Acs chemical biology
JF - Acs chemical biology
SN - 1554-8929
ER -