Evaluation of Potent Isoquinoline-Based Thiosemicarbazone Antiproliferatives Against Solid Tumor Models

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.