Discovery and biological evaluation of ferroptocide

Llabani, Evijola

Permalink

https://hdl.handle.net/2142/105125 Copy

Description

Title

Discovery and biological evaluation of ferroptocide

Author(s)

Llabani, Evijola

Issue Date

2019-01-16

Director of Research (if dissertation) or Advisor (if thesis)

Hergenrother, Paul J.

Doctoral Committee Chair(s)

Hergenrother, Paul J.

Committee Member(s)

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

Department of Study

Chemistry

Discipline

Chemistry

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

ferroptosis, thioredoxin

Abstract

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.

Graduation Semester

2019-05

Type of Resource

text

Permalink

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

Copyright and License Information

Copyright Evijola Llabani 2019

Owning Collections