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Evaluation of Potent Isoquinoline-Based Thiosemicarbazone Antiproliferatives Against Solid Tumor Models
preprintsubmitted on 22.03.2019, 22:40 and posted on 25.03.2019, 16:53 by Daniel Sun, Soumya Poddar, Roy D. Pan, Juno Van Valkenburgh, Ethan Rosser, Evan Abt, Vincent Lok, Joseph Capri, Selena Hernandez, Janet Song, Joanna Li, Laurent Vergnes, Anthony Cabebe, Wesley Armstrong, Sheba Plamthottam, Dalton Steele, Corey Osto, Andreea Stuparu, Thuc Le, Karen Reue, Robert Damoiseaux, Johanes Czernin, Michael Jung, Caius Radu
The lead compound, an ⍺-N-heterocyclic carboxaldehyde thiosemicarbazone HCT-13, was highly potent against a panel of pancreatic, small cell lung carcinoma, and prostate cancer models, with IC90 values in the low-to-mid nanomolar range. We show that the cytotoxicity of HCT-13 is copper-dependent, that it acts as a copper ionophore, induces production of reactive oxygen species (ROS), and promotes mitochondrial dysfunction and S-phase arrest. Lastly, DNA damage response/replication stress response (DDR/RSR) pathways, specifically Ataxia-Telangiectasia Mutated (ATM) and Rad3-related protein kinase (ATR), were identified as actionable adaptive resistance mechanisms following HCT-13 treatment. Taken together, HCT-13 is potent against solid tumor models and warrants in vivo evaluation against aggressive tumor models, either as a single agent or as part of a combination therapy.
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