Related Experiment Video
Updated: Dec 18, 2025
In Silico Modeling Method for Computational Aquatic Toxicology of Endocrine Disruptors: A Software-Based Approach Using QSAR Toolbox
Published on: August 28, 2019
Preclinical toxicology profile of squalene epoxidase inhibitors
Raj Nagaraja1, Andrew Olaharski1, Rohini Narayanaswamy1
1Agios Pharmaceuticals, Inc., 88 Sidney St, Cambridge, MA 02139, USA.
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.
Insights
Small cell lung cancer (SCLC) therapies are limited. Squalene epoxidase (SQLE) inhibition shows promise, but toxicity studies in dogs and monkeys reveal significant gastrointestinal and skin toxicities at sub-therapeutic doses.
Area of Science:
- Oncology
- Biochemistry
- Pharmacology
Background:
- Small cell lung cancer (SCLC) is an aggressive malignancy with limited therapeutic options.
- SCLC cell lines exhibit a specific vulnerability to squalene epoxidase (SQLE) inhibition.
- SQLE is a key enzyme in the cholesterol biosynthesis pathway, converting squalene to 2,3-oxidosqualene.
Purpose of the Study:
- To evaluate the tolerability of SQLE inhibitors at exposures predicted for maximal anti-tumor efficacy in SCLC.
- To investigate potential dose-limiting toxicities associated with SQLE inhibition in preclinical models.
- To assess the therapeutic window for SQLE inhibitors in SCLC treatment.
Main Methods:
- Profiling of SQLE inhibitors (NB-598, Cmpd-4″) and their inactive analogs in canine and non-human primate models.
- Assessment of clinical observations and toxicities at various dose levels.
- Comparison of toxicities between active inhibitors and inactive analogs.
Main Results:
- Dogs exhibited dose-limiting gastrointestinal and skin toxicities with NB-598 at predicted efficacious exposures.
- Monkeys treated with NB-598 and Cmpd-4″ showed dose-limiting gastrointestinal toxicity.
- Structurally similar inactive analogs did not produce significant toxicities in monkeys.
- Toxicities were observed at exposures well below those required for anti-tumor activity.
Conclusions:
- On-target toxicities associated with SQLE inhibition, particularly gastrointestinal effects, limit therapeutic utility in SCLC.
- The therapeutic window for SQLE inhibitors in SCLC is narrow, hindering clinical application.
- Further research is needed to identify strategies to mitigate SQLE inhibitor-related toxicities for SCLC treatment.
