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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