CP-24,879: an activity-based probe of fatty acid desaturases and related diiron lipid oxidases.

ABSTRACT: Abstract: CP-24,879 inhibits fatty acid desaturase 2 (FADS2), a diiron lipid oxidase necessary for polyunsaturated fatty acid (PUFA) biosynthesis, with exceptional cellular potency (EC50 15 nM) despite its fragment-like structure. Here we demonstrate CP-24,879 is unexpectedly activated in cells to a reactive intermediate that covalently targets FADS2 with remarkable proteome-wide selectivity. No proteome labeling is observed in the absence of FADS2 activity, supporting FADS2 as directly activating CP-24,879. CP-24,879 also covalently labeled fatty acid desaturase 1 (FADS1) in cells with active FADS1, consistent with CP-24,879’s established lower potency for inhibition of FADS1. Analysis of four additional diiron lipid oxidases identified two family members, DEGS1 and MSMO1, that were also targeted by CP-24,879. Together these studies define the mechanism-of-action of CP-24,879 and establish a new activity-based probe of diiron lipid oxidases, creating new opportunities for advancing the chemical biology of this understudied protein family.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hek-293 Cell

SUBMITTER: Belinda Willard  

LAB HEAD: Drew Adams Ph.D.

PROVIDER: PXD078603 | Pride | 2026-09-28

REPOSITORIES: Pride