Bempedoic acid | ATP citrate lyase inhibitor

Bempedoic acid (738606-46-7) is an inhibitor of ATP citrate lyase (ACL) and activator of AMPK used in the treatment of hypercholesterolemia.^1,2 In vivo, the active molecule is the CoA ester.² Bempedoic acid requires activation by very long-chain acyl-CoA-synthetase (ACSVL1) – the absence of ACSVL1 in skeletal muscle provides a mechanistic basis for its use in statin-intolerant patients.³ LDL receptor upregulation, decreased LDL-C, and attenuation of atherosclerosis activities are independent of AMPK activation. It significantly cuts the risk of major cardiovascular events.⁴ Combination treatment of breast and pancreatic cancer cell lines with bempedoic acid and CDK4/6 inhibitors reduced cell growth and invasion.⁵ It displays anti-inflammatory activity possibly through both ACL inhibition^6,7 and AMPK activation⁸.

References/Citations:

1. Cramer et al. (2004), Effects of a novel dual lipid synthesis inhibitor and its potential utility in treating dyslipidemia and metabolic syndrome; J. Lipid Res., 45 P1289
2. Pinkosky et al. (2013), AMP-activated protein kinase and ATP-citrate lyase are two distinct molecules targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism; J. Lipid Res., 54 134
3. Pinkosky et al. (2016), Liver-specific ATP-citrate lyase inhibition by bempedoic aicd decreases LDL-C and attenuates atherosclerosis; Nat. Commun., 7 13457
4. Nissen et al. (2023), Bempedoic acid and cardiovascular outcomes in statin-intolerant patients; N. Engl. J. Med., online March 4, 2023
5. Velez et al. (2023), Combined inhibition of ACLY and CDK4/6 reduces cancer cell growth and invasion; Oncol. Rep., 49 32
6. Samsoonday et al. (2017), Prevention of Diet-Induced metabolic dysregulation, inflammation, and atherosclerosis in ldlr-/- mice by treatment with the ATP-Citrate lyase inhibitor bempedoic acid; Arterioscler. Thromb. Vasc. Biol., 37 647
7. Verberk et al. (2021), The multifaceted therapeutic value of targeting ATP-citrate lyase in atherosclerosis; Trends Mol. Med., 27 1095
8. Filippov et al. (2013), ETC-1002 regulates immune response, leukocyte homing, and adipose tissue inflammation via LKB1-dependent activation of macrophage AMPK; J. Lipid Res., 54 2095