EVT0185 (EVT-0185) is a novel, orally available small molecule inhibitor of ATP citrate lyase (ACLY), inhibits de novo lipogenesis with IC50 of 0.46 uM in mouse primary hepatocytes.
EVT0185 is activated in hepatocytes via SLC27A2-dependent conversion to its CoA-thioester form (EVT0185-CoA), allowing liver-specific action while sparing non-hepatic tissues.
EVT0185-CoA directly interacts with the CoA-binding site of ACLY.
EVT0185 more potently inhibits fatty acid and cholesterol synthesis from lactate and acetate than bempedoic acid (Cat#PC-43001) in WT hepatocytes.
EVT0185-CoA inhibits rather than activated AMPKβ1-containing complexes, and also inhibits ACC1, ACC2 and ACSS2.
EVT0185 also suppresses clonogenic survival of human (Hep3B) and mouse (Hepa1-6) HCC cell lines more effectively than bempedoic acid.
EVT0185 (100 mg/kg) reduces tumour burden in distinct mouse models of MASH-HCC, promotes tumour-infiltrating B cells.