Preclinical toxicology profile of squalene epoxidase inhibitors

Toxicol Appl Pharmacol. 2020 Aug 15:401:115103. doi: 10.1016/j.taap.2020.115103. Epub 2020 Jun 6.

Abstract

Small cell lung cancer (SCLC) is a particularly aggressive subset of lung cancer, and identification of new therapeutic options is of significant interest. We recently reported that SCLC cell lines display a specific vulnerability to inhibition of squalene epoxidase (SQLE), an enzyme in the cholesterol biosynthetic pathway that catalyzes the conversion of squalene to 2,3-oxidosqualene. Since it has been reported that SQLE inhibition can result in dermatitis in dogs, we conducted a series of experiments to determine if SQLE inhibitors would be tolerated at exposures predicted to drive maximal efficacy in SCLC tumors. Detailed profiling of the SQLE inhibitor NB-598 showed that dogs did not tolerate predicted efficacious exposures, with dose-limiting toxicity due to gastrointestinal clinical observations, although skin toxicities were also observed. To extend these studies, two SQLE inhibitors, NB-598 and Cmpd-4″, and their structurally inactive analogs, NB-598.ia and Cmpd-4″.ia, were profiled in monkeys. While both active SQLE inhibitors resulted in dose-limiting gastrointestinal toxicity, the structurally similar inactive analogs did not. Collectively, our data demonstrate that significant toxicities arise at exposures well below the predicted levels needed for anti-tumor activity. The on-target nature of the toxicities identified is likely to limit the potential therapeutic utility of SQLE inhibition for the treatment of SCLC.

Keywords: SCLC; SQLE; Small Cell Lung Cancer; Squalene Epoxidase Inhibitor; Toxicity; Tumor Metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dogs
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical / methods
  • Enzyme Inhibitors / blood*
  • Enzyme Inhibitors / toxicity*
  • Macaca fascicularis
  • Male
  • Skin / drug effects
  • Skin / enzymology
  • Skin / pathology
  • Squalene Monooxygenase / antagonists & inhibitors*
  • Squalene Monooxygenase / blood*

Substances

  • Enzyme Inhibitors
  • Squalene Monooxygenase