Discovery and biological evaluation of ferroptocide

The chemical diversification of natural products provides a robust and general method for creation of stereochemically complex and structurally diverse small molecules. The resulting compounds have physicochemical traits different from those in most screening collections, and as such are a rich source for biological discovery. Herein, we subject the complexity-to-diversity library of compounds to an anticancer phenotypic screen. This effort resulted in identification of an active class of compounds derived from pleuromutilin natural product. Biological evaluation identified the novel compound ferroptocide, a small molecule that rapidly and robustly induces ferroptotic death of cancer cells. Target identification efforts and CRISPR knockout studies reveal that ferroptocide has a different target from other known pro-ferroptotic agents; it is an inhibitor of thioredoxin, a key component of the thioredoxin antioxidant system in the cell. Ferroptocide shows the ability to positively modulate the immune system in a murine model of breast cancer and will be a useful tool to study the utility of pro-ferroptotic agents for treatment of cancer.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2019

Author dc:creator

• Llabani, Evijola

Contributors dc:contributor

• Hergenrother, Paul J.
• Chan, Jefferson
• van der Donk, Wilfred
• Zimmerman, Steven C.

• ferroptosis, thioredoxin

Statement dc:rights

• Copyright Evijola Llabani 2019

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/105125

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/105125