Affiliation:Director, Human Health and Environment Program, Desert Research Institute Summerlin, 10530 Discovery Drive, Las Vegas, NV 89135, USA. J Cell Physiol 2012; 227: 1709 – 20. A role for ATP Citrate Lyase in cell cycle regulation during myeloid differentiation. ATP citrate lyase inhibitors as novel cancer therapeutic agents. To date only partial X-ray structures of ACLY have been solved, thus limiting the design of novel inhibitors. T3625 CAS 738606-46-7 . 2011 Oct 1;67(Pt 10):1168-72. doi: 10.1107/S1744309111028363. To investigate the effect of ACLY inhibition on lipid metabolism, metabolome and transcriptome analysis was performed. Answer: (a, b, c, and e). Bempedoic acid is a prodrug.It is activated to the thioester with coenzyme A by the enzyme SLC27A2 in the liver. No. Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis Stephen L. Pinkosky1,2, Roger S. Newton1, Emily A. Day2, Rebecca J. Ford2, Sarka Lhotak3, Richard C. Austin3, Carolyn M. Birch1, Brennan K. Smith2, Sergey Filippov1, Pieter H.E. It is an ATP Citrate Lyase (ACL) inhibitor. Neuroscience ATP Citrate Lyase ETC-1002 ETC-1002. 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. e. Hyperuricemia and increased risk of tendon rupture or injury is reported side effect of the drug. ATP-citrate lyase (ACLY) is an enzyme that links glycolysis to lipid metabolism. NDI-091143 inhibits ACLY catalysis allosterically, by stabilizing large conformational changes in the citrate domain that indirectly block the binding and recognition of citrate. Acta Crystallogr Sect F Struct Biol Cryst Commun. Summary: ATP citrate lyase is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues. It is one of the major sources of cytosolic acetyl-CoA, and is a central metabolic enzyme. Bempedoic acid (BA; ETC-1002) is a new agent that reduces cholesterol synthesis through inhibition of adenosine triphosphate citrate lyase, an enzyme upstream from 3-hydroxy-3-methylglutaryl-coenzyme A.In animal models, BA also influences fatty acid synthesis, but in humans, its role is limited primarily to lowering low-density lipoprotein cholesterol (LDL-C). NONSTATIN DRUGS (E. DEGOMA, SECTION EDITOR) Bempedoic Acid (ETC-1002): an Investigational Inhibitor of ATP Citrate Lyase Ozlem Bilen1,3 & Christie M. Ballantyne1,2,3 # The Author(s) 2016. Curr Atheroscler Rep. 2016; 18(10):61 (ISSN: 1534-6242) Bilen O; Ballantyne CM. • Lead compound 1d inhibited A549 lung cancer cell proliferation and reduced the stemness of A549 cells.. Docking suggested that anthraquinone inhibitors occupied an allosteric site adjacent to the citrate-binding domain of ACL. ATP-citrate lyase (ACLY) inhibitor with an IC 50 of 2.1 nM (ADP-Glo assay), a K of 7.0 nM and a i K of 2.2 nM. The active ingredient found in Nexletol is Bempedoic acid. It catalyzes the formation of acetyl-CoA and oxaloacetate from citrate and CoA with a concomitant hydrolysis of ATP to ADP and phosphate. NDI-091143 is a potent and high-affinity human ATP-citrate lyase (ACLY) inhibitor with an IC50 of 2.1 nM (ADP-Glo assay), a Ki of 7.0 nM and a Kd of 2.2 nM. Chemical inhibitors such as BMS-303141 is a potent, cell-permeable ATP-citrate lyase (ACL) inhibitor with an IC50 value of 0.13 μM. Author(s):Xu-Yu Zu, Qing-Hai Zhang, Jiang-Hua Liu, Ren-Xian Cao, Jing Zhong, Guang-Hui Yi, Zhi-Hua Quan and Giuseppe Pizzorno. d. The recommended dose should be taken every 8 hours. Sun T, Hayakawa K, Fraser ME: ADP-Mg2+ bound to the ATP-grasp domain of ATP-citrate lyase. Abstract ATP citrate lyase (ACLY), a key enzyme in the metabolic reprogramming of many cancers, is widely expressed in various mammalian tissues. Studies were performed with recombinant human ACL to ascertain the nature of the catalytic phosphorylation that initiates the ACL reaction and the identity of the active site residues involved. It is a tablet, an oral, once-daily, non-statin (LDL-C) lowering medicine. The activated substance inhibits ATP citrate lyase, which is involved in the liver's biosynthesis of cholesterol upstream of HMG-CoA reductase, the enzyme that is blocked by statins.. ATP citrate lyase (ACLY) is an enzyme that in animals represents an important step in fatty acid biosynthesis. ATP citrate lyase is an enzyme in the cholesterol–biosynthesis pathway located upstream of 3-hydroxy-3-methylglutaryl–coenzyme A reductase (HMGCR). Bempedoic acid (ETC-1002), a novel therapeutic approach for low-density lipoprotein cholesterol (LDL-C) lowering, inhibits ATP citrate lyase (ACL), an enzyme involved in fatty acid and cholesterol synthesis. Many tumors display a high rate of glucose utilization, as evidenced by 18-F-2-deoxyglucose PET imaging. Title:ATP Citrate Lyase Inhibitors as Novel Cancer Therapeutic Agents. Bempedoic acid (ETC-1002), a novel therapeutic approach for low-density lipoprotein cholesterol (LDL-C) lowering, inhibits ATP citrate lyase (ACL), an enzyme involved in fatty acid and cholesterol synthesis. VOLUME: 7 ISSUE: 2. : HY-16450 SB 204990 is a potent and specific inhibitor of ATP citrate lyase (ACLY) enzyme. Bempedoic Acid (ETC-1002): an Investigational Inhibitor of ATP Citrate Lyase. NDI-091143 is a potent inhibitor of human ATP-citrate lyase(ACLY) with a Ki of 7.0 nM and an IC50 of 2.1 nM in the ADP-Glo assay. Rhee J(1), Solomon LA(1), DeKoter RP(2). ATP-citrate lyase (ACLY) catalyzes the ATP-dependent conversion of citrate and CoA to oxaloacetate and acetyl-CoA. Objective: Bempedoic acid (BemA; ETC-1002) is a novel drug that targets hepatic ATP-citrate lyase to reduce cholesterol biosynthesis. Epub 2011 Sep 24. 2012; 7(2):154-67 (ISSN: 2212-3970) Zu XY; Zhang QH; Liu JH; Cao RX; Zhong J; Yi GH; Quan ZH; Pizzorno G. ATP citrate lyase (ACL or ACLY) is an extra-mitochondrial enzyme widely distributed in various human and animal tissues. Inhibition of lung cancer growth: ATP citrate lyase knockdown and statin treatment leads to dual blockade of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)/AKT pathways. Purity 99.94% Datasheet. Methods of inducing apoptosis in cancer cells using an ATP citrate lyase inhibitor and/or tricarboxylate transporter inhibitor are disclosed. ATP citrate lyase (ACLY) is an important enzyme that catalyzes the conversion of citrate to acetyl-CoA in normal cells, facilitating the de novo fatty acid synthesis. novel bioactive compounds, analogs & targets. BMS-303141 shows inhibition of total lipid syntheses with IC50 of 8 μM in HepG2 cells. Although rodent studies suggested potential effects of ACL inhibition on both fatty acid and cholesterol synthesis, studies in humans show an effect only on cholesterol synthesis. The enzyme is a tetramer (relative molecular weight approximately 440,000) of apparently identical subunits. One potential advantage of catabolizing glucose through glycolysis at a rate that exceeds bioenergetic need is that the growing cell can redirect the excess glycolytic end product pyruvate toward lipid synthesis. Recent Pat Anticancer Drug Discov. ACLY depletion by small interfering RNAs caused growth suppression and/or apoptosis in a subset of cancer cell lines. [PubMed:22102020] Drug Relations Drug Relations BMS-303141 is a potent, cell-permeable inhibitor of ATP-citrate lyase (ACL) with IC50 of 0.13 μM. Lipids and fatty acids were found to be accumulated in different types of tumors, such as brain, breast, rectal and ovarian cancer, representing a great source of energy for cancer cell growth and metabolism. Methods of treating individuals identified as having cancer using ATP citrate lyase inhibitor and/or tricarboxylate transporter inhibitor are disclosed. It can inhibit the growth and progression of prostate cancer cells and play a corresponding inhibitory effect in animal models. Synonyms: ETC1002, ETC 1002, Bempedoic acid, ESP-55016. Catalog No. ATP-citrate lyase (ACL) is an extramitochondrial enzyme that is expressed in lipogenic tissues such as liver and adipose. By converting citrate to acetyl-CoA, the enzyme links carbohydrate metabolism, which yields citrate as an intermediate, with fatty acid biosynthesis, which consumes acetyl-CoA. Here, we demonstrate a novel function of the lipogenic enzyme, ATP citrate lyase (ACLY), in lipid metabolism in cancer cells. The acetyl-CoA product is crucial for fatty acid metabolism, cholesterol biosynthesis, and post-translational modification of proteins (acetylation and prenylaion). Recent Patents on Anti-Cancer Drug Discovery publishes review articles on recent patents in the field of anti-cancer drug discovery e.g. d Purity: 99.72% Clinical Data:No Development Reported Size: 10 mM × 1 mL, 5 mg, 10 mg SB 204990 Cat. What’s more, small interfering RNAs have been used to down-regulate the expression of ATP citrate lyase. Emodin anthraquinones inhibited the enzymatic activity ATP-citrate lyase (ACL), a key player in cancer cell metabolism. 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