Abstract 2755: Identification of novel GPX4 inhibitors using global transcriptional reporters

• Published in: Cancer research (Chicago, Ill.) Ill.), 2023-04, Vol.83 (7_Supplement), p.2755-2755
• Main Authors: Read, Timothy, Winigrad, Zoe, Goliaei, Ardeshir, Liechty, Cole, Grochala, Carter, Damon, Leah, Dickson, John, Harris, Jason, Pham, Casey, Rimel, Jenna, Rhine, Christy, Simpson, Dave, Martin, Eric, Azofeifa, Joey
• Format: Article
• Language: English
• ISSN: 1538-7445; 1538-7445
• DOI: 10.1158/1538-7445.AM2023-2755

Induction of Ferroptosis is a promising strategy for treating therapy-resistant tumors including mesenchymal tumor types. We performed a phenotypic screen to identify small molecules that induce ferroptosis in mesenchymal cancer cells by screening for compounds whose toxicity could be rescued by the lipophilic antioxidant Ferrostatin-1. To identify compounds that induce GPX4-mediated ferroptosis, we identified several pharmacodynamic biomarkers specific to GPX4 inhibition using our nascent RNA sequencing platform, which allows for time-resolved snapshots of global transcription. We measured the transcriptional changes that occur in the hours following inhibition of GPX4 and identified HMOX1 as a robust biomarker of GPX4i-induced ferroptosis in mesenchymal cancer cell lines. Using HMOX1-induction as a guide, we uncovered a small number of compounds as potential GPX4 inhibitors. One such compound was validated as a bonafide GPX4 inhibitor through a variety of biochemical assays and selected for a hit-to-lead campaign. In addition to standard medicinal chemistry strategies, we are currently employing a newly-developed global transcriptional reporter system to stratify several novel series of GPX4 inhibitors by their transcriptional signatures. This approach represents a unique strategy for determining on- and off- target effects of a compound and for defining structure activity relationships within a chemical series. Citation Format: Timothy Read, Zoe Winigrad, Ardeshir Goliaei, Cole Liechty, Carter Grochala, Leah Damon, John Dickson, Jason Harris, Casey Pham, Jenna Rimel, Christy Rhine, Dave Simpson, Eric Martin, Joey Azofeifa. Identification of novel GPX4 inhibitors using global transcriptional reporters [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2755.