Inhibition of human mevalonate kinase by allosteric inhibitors of farnesyl pyrophosphate synthase

• Published in: FEBS open bio Vol. 14; no. 8; pp. 1320 - 1339
• Main Authors: Salari, Saman, Lee, Hiu‐Fung, Tsantrizos, Youla S., Park, Jaeok
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.08.2024; John Wiley and Sons Inc; Wiley
• Subjects: Allosteric properties; Allosteric Regulation - drug effects; Alzheimer's disease; Cancer therapies; Chromatography; Dehydrogenases; Enzyme inhibitors; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzyme Kinetics; Enzymes; farnesyl pyrophosphate; Farnesyl pyrophosphate synthase; Feedback; Feedback inhibition; Geranyltranstransferase - antagonists & inhibitors; Geranyltranstransferase - metabolism; Humans; isoprenoid synthesis; Kinases; Kinetics; Metabolites; Mevalonate kinase; Mevalonate pathway; Pharmacology; phosphonate compounds; Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Polyisoprenyl Phosphates - metabolism; Sesquiterpenes - chemistry; Sesquiterpenes - metabolism; Sesquiterpenes - pharmacology; Signal transduction; Software; Therapeutic targets; Canada; phosphonate compounds; isoprenoid synthesis; mevalonate pathway; mevalonate kinase; farnesyl pyrophosphate; feedback inhibition
• ISSN: 2211-5463; 2211-5463
• DOI: 10.1002/2211-5463.13853

Mevalonate kinase is a key regulator of the mevalonate pathway, subject to feedback inhibition by the downstream metabolite farnesyl pyrophosphate. In this study, we validated the hypothesis that monophosphonate compounds mimicking farnesyl pyrophosphate can inhibit mevalonate kinase. Exploring compounds originally synthesized as allosteric inhibitors of farnesyl pyrophosphate synthase, we discovered mevalonate kinase inhibitors with nanomolar activity. Kinetic characterization of the two most potent inhibitors demonstrated Ki values of 3.1 and 22 nm. Structural comparison suggested features of these inhibitors likely responsible for their potency. Our findings introduce the first class of nanomolar inhibitors of human mevalonate kinase, opening avenues for future research. These compounds might prove useful as molecular tools to study mevalonate pathway regulation and evaluate mevalonate kinase as a potential therapeutic target. Mevalonate kinase constitutes a key regulatory step in the mevalonate pathway, an established drug target for its role in the synthesis of isoprenoid molecules. Using a structure‐based rational approach, we identified several synthetic compounds that inhibit mevalonate kinase with nanomolar potency. Further analysis revealed their mode of inhibition and the structural features that correlate with their inhibitory potency.