The first potent COQ8 inhibitor targets ubiquinone biosynthesis

Discovery cascade to identify and validate TPP-UNC-CA157. Credit: Christopher Asquith

A new joint study by the University of Eastern Finland, Washington University in St. Louis, University of Wisconsin-Madison, University of North Carolina at Chapel Hill and the Promega Corporation reveals the discovery and application of a novel chemical probe to selectively detect human COQ8A brakes in cells. The results have been published in Nature Chemical Biology.

Protein kinases are enzymes that catalyze the phosphate transfer from adenosine triphosphate (ATP) to tyrosine, threonine or serine residues in specific target proteins. These phosphorylation events occur in nearly every signal transduction pathway and provide regulatory points for therapeutic intervention. Kinases have been successfully used as drug targets over the past 30 years, with nearly 90 kinase inhibitors approved by the FDA, primarily for the treatment of cancer and inflammatory diseases.

The canonical function of kinases is phosphorylation, but nearly 10% of annotated kinases lack enzymatic activity. Despite being catalytically inactive, these pseudo-kinases perform numerous non-canonical kinase functions through their inactive ATP-binding domain. A subfamily of these pseudo-kinases are the UbiB proteins, including the kinase COQ8B and pseudo-kinase COQ8A, whose mutations are directly associated with multiple human diseases, such as autosomal recessive cerebellar ataxia and steroid-resistant nephrotic syndrome.

To date, the only clear link between UbiB proteins and biological processes is the requirement of Coq8 for coenzyme Q (CoQ) biosynthesis in yeast cells. The full characterization of Coq8 and other UbiB proteins has been hampered by a lack of powerful, selective chemical tools to investigate their biological functions. In this new work, the researchers reveal a highly specific potent inhibitor TTP-UNC-CA157, which targets the human COQ8 proteins and is the first small molecule inhibitor of COQ8A or COQ8B to demonstrate effects on their known roles in CoQ biosynthesis in cells .

To identify lead inhibitor compounds, the researchers searched published kinase screening data and found COQ8A as a promising secondary target for 4-anilinoquinolines. After a series of screenings, UNC-CA157 was selected as the most promising lead candidate for further development. In the course of the research, the team solved a co-crystal structure of COQ8A bound to UNC-CA157. This structure helped their medicinal chemistry efforts to specifically target this compound to the mitochondrial matrix through the addition of triphenylphosphonium (TPP) to the solvent-exposed region of UNC-CA157. They also demonstrated the efficacy of the mitochondria-targeted inhibitor in a cellular context, which is essential for wider utility within the field.

While cells depend on CoQ biosynthesis for respiration and other metabolic processes, there are potential benefits to inhibition. Limitations of CoQ production by genetic or nutritional intervention increase longevity in Caenorhabditis elegans and mice. CoQ is also used by the oxidoreductase FSP1 to help inhibit cancer cell death, suggesting that cell-specific suppression of CoQ biosynthesis may be an effective anti-cancer strategy. The small molecule inhibitors developed and characterized in this work provide a starting point for the implementation of COQ8 inhibition in these areas and for a more comprehensive investigation of their cellular functions and the beginning of a potential therapeutic strategy.

More information:
Nathan H. Murray et al, Small molecule inhibition of the archetypal UbiB protein COQ8, Nature Chemical Biology (2022). DOI: 10.1038/s41589-022-01168-3

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