Monday, March 30, 2020

Selective covalent targeting of GPX4 using masked nitrile-oxide electrophiles

John K. Eaton, Laura Furst, Richard A. Ruberto, Dieter Moosmayer, André Hilpmann, Matthew J. Ryan, Katja Zimmermann, Luke L. Cai, Michael Niehues, Volker Badock, Anneke Kramm, Sixun Chen, Roman C. Hillig, Paul A. Clemons, Stefan Gradl, Claire Montagnon, Kiel E. Lazarski, Sven Christian, Besnik Bajrami, Roland Neuhaus, Ashley L. Eheim, Vasanthi S. Viswanathan & Stuart L. Schreiber

Nature Chemical Biology,  2020


We recently described glutathione peroxidase 4 (GPX4) as a promising target for killing therapy-resistant cancer cells via ferroptosis. The onset of therapy resistance by multiple types of treatment results in a stable cell state marked by high levels of polyunsaturated lipids and an acquired dependency on GPX4. Unfortunately, all existing inhibitors of GPX4 act covalently via a reactive alkyl chloride moiety that confers poor selectivity and pharmacokinetic properties. Here, we report our discovery that masked nitrile-oxide electrophiles, which have not been explored previously as covalent cellular probes, undergo remarkable chemical transformations in cells and provide an effective strategy for selective targeting of GPX4. The new GPX4-inhibiting compounds we describe exhibit unexpected proteome-wide selectivity and, in some instances, vastly improved physiochemical and pharmacokinetic properties compared to existing chloroacetamide-based GPX4 inhibitors. These features make them superior tool compounds for biological interrogation of ferroptosis and constitute starting points for development of improved inhibitors of GPX4.

Oncogenic KRAS G12C: Kinetic and Redox Characterization of Covalent Inhibition

Minh V. Huynh, Derek Parsonage, Tom E. Forshaw, Venkat R. Chirasani, G. Aaron Hobbs, Hanzhi Wu, Jingyun Lee, Cristina M. Furdui, Leslie B. P...