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

25 March 2019, Version 1

Abstract

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.

Keywords

thiosemicarbazone
HCT
IQ1
IQ-1
PDAC
PC
prostate cancer
HCT-13
anticancer
Antiproliferative

Supplementary materials

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HCT SI Final 03212019
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