NDI-091143

ATP-citrate lyase (ACLY) is an enzyme that links glycolysis to lipid metabolism. To date only partial X-ray structures of ACLY have been solved, thus limiting the design of novel inhibitors. Wei and colleagues (published online in Nature April 3, 2019) now report the full structure of human ACLY in complex with NDI-091143, revealing an appealing allosteric inhibition mechanism for this compound.

ATP-citrate lyase (ACLY) is a central metabolic enzyme and catalyses the ATP-dependent conversion of citrate and coenzyme A (CoA) to oxaloacetate and acetyl-CoA^1-5. The acetyl-CoA product is crucial for the metabolism of fatty acids^6,7, the biosynthesis of cholesterol⁸, and the acetylation and prenylation of proteins^9,10. There has been considerable interest in ACLY as a target for anti-cancer drugs, because many cancer cells depend on its activity for proliferation^2,5,11. ACLY is also a target against dyslipidaemia and hepatic steatosis, with a compound currently in phase 3 clinical trials^4,5. Many inhibitors of ACLY have been reported, but most of them have weak activity⁵. Here we report the development of a series of low nanomolar, small-molecule inhibitors of human ACLY. We have also determined the structure of the full-length human ACLY homo-tetramer in complex with one of these inhibitors (NDI-091143) by cryo-electron microscopy, which reveals an unexpected mechanism of inhibition. The compound is located in an allosteric, mostly hydrophobic cavity next to the citrate-binding site, and requires extensive conformational changes in the enzyme that indirectly disrupt citrate binding. The observed binding mode is supported by and explains the structure-activity relationships of these compounds. This allosteric site greatly enhances the 'druggability' of ACLY and represents an attractive target for the development of new ACLY inhibitors.