Cathepsin L (CatL) is one of the lysosomal proteolytic enzymes expressed in high levels in many malignant tumors, including hepatocarcinoma. There are limited therapeutic options to treat advanced malignant hepatocellular carcinoma (HCC). CatL has been investigated as a diagnostic marker and as a drug target for potential cancer therapeutics. In this work, the biochemical actions, the antiproliferative effects, and the ADME properties of new CatL inhibitors were investigated. The project's long-term goal is to facilitate the discovery and development of the CatL inhibitors and analogs as new anti-hepatocellular carcinoma agents. The antiproliferative activities of the inhibitors were investigated through dose-dependent cell viability and migration assays using Hep G2 and Hep 3B cell lines. CatL inhibition was studied using recombinant CatL and endogenous CatL in live cells and lysates from Hep G2 cells. Drug target selectivity was assessed using recombinant Cathepsin B and endogenous cathepsin B in live cells and lysates from Hep G2. In addition, the reactive oxygen species (ROS)-generating capacity of the compounds were assessed in HCC (Hep G2 and Hep 3B). Preliminary in vitro ADME assays were also carried out. The inhibitors have antiproliferative effects on Hep G2 and Hep 3B cell lines with low micromolar IC<sub>50</sub> values. In addition, the key compound can inactivate recombinant and endogenous CatL in a time-dependent manner. Furthermore, the key inhibitor has bidirectional cellular permeability, and it is not a substrate of the P-glycoprotein efflux pump (P-gp). On-going studies are focused on xenograft and pharmacokinetics experiments in mice in addition to medicinal chemistry optimization studies. Overall, the series of CatL inhibitors under investigation appears to be good candidates for optimization as potential HCC agents.

Biochemical and therapeutic actions of cathepsin L (CatL) inhibitors against hepatocellular carcinoma

ACS Spring 2022

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