Small-molecule inhibition of the archetypal UbiB protein COQ8

Nathan H. Murray, Christopher R.M. Asquith, Zixiang Fang, Michael P. East, Naomi Ptak, Robert W. Smith, James D. Vasta, Chad A. Zimprich, Cesear R. Corona, Matthew B. Robers, Gary L. Johnson, Craig A. Bingman, David J. Pagliarini

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Small-molecule tools have enabled mechanistic investigations and therapeutic targeting of the protein kinase-like (PKL) superfamily. However, such tools are still lacking for many PKL members, including the highly conserved and disease-related UbiB family. Here, we sought to develop and characterize an inhibitor for the archetypal UbiB member COQ8, whose function is essential for coenzyme Q (CoQ) biosynthesis. Guided by crystallography, activity assays and cellular CoQ measurements, we repurposed the 4-anilinoquinoline scaffold to selectively inhibit human COQ8A in cells. Our chemical tool promises to lend mechanistic insights into the activities of these widespread and understudied proteins and to offer potential therapeutic strategies for human diseases connected to their dysfunction. [Figure not available: see fulltext.]

Original languageEnglish
Pages (from-to)230-238
Number of pages9
JournalNature Chemical Biology
Issue number2
StatePublished - Feb 2023


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