• 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. Recent Pat Anticancer Drug Discov. Methods of treating individuals identified as having cancer using ATP citrate lyase inhibitor and/or tricarboxylate transporter inhibitor are disclosed. Recent Patents on Anti-Cancer Drug Discovery publishes review articles on recent patents in the field of anti-cancer drug discovery e.g. ATP citrate lyase is an enzyme in the cholesterol–biosynthesis pathway located upstream of 3-hydroxy-3-methylglutaryl–coenzyme A reductase (HMGCR). The enzyme is a tetramer (relative molecular weight approximately 440,000) of apparently identical subunits. Catalog No. J Cell Physiol 2012; 227: 1709 – 20. Keywords:ACL inhibitors, ATP … BMS-303141 is a potent, cell-permeable inhibitor of ATP-citrate lyase (ACL) with IC50 of 0.13 μM. Emodin anthraquinones inhibited the enzymatic activity ATP-citrate lyase (ACL), a key player in cancer cell metabolism. 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. T3625 CAS 738606-46-7 . Many tumors display a high rate of glucose utilization, as evidenced by 18-F-2-deoxyglucose PET imaging. d Purity: 99.72% Clinical Data:No Development Reported Size: 10 mM × 1 mL, 5 mg, 10 mg SB 204990 Cat. 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. It is a tablet, an oral, once-daily, non-statin (LDL-C) lowering medicine. Here, we demonstrate a novel function of the lipogenic enzyme, ATP citrate lyase (ACLY), in lipid metabolism in cancer cells. Summary: ATP citrate lyase is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues. 2011 Oct 1;67(Pt 10):1168-72. doi: 10.1107/S1744309111028363. VOLUME: 7 ISSUE: 2. 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. ACLY depletion by small interfering RNAs caused growth suppression and/or apoptosis in a subset of cancer cell lines. 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. 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. Bempedoic acid is a prodrug.It is activated to the thioester with coenzyme A by the enzyme SLC27A2 in the liver. Abstract ATP citrate lyase (ACLY), a key enzyme in the metabolic reprogramming of many cancers, is widely expressed in various mammalian tissues. 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. 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. No. Neuroscience ATP Citrate Lyase ETC-1002 ETC-1002. ATP-citrate lyase (ACL) is an extramitochondrial enzyme that is expressed in lipogenic tissues such as liver and adipose. Answer: (a, b, c, and e). Purity 99.94% Datasheet. Affiliation:Director, Human Health and Environment Program, Desert Research Institute Summerlin, 10530 Discovery Drive, Las Vegas, NV 89135, USA. ATP citrate lyase (ACLY) is an enzyme that in animals represents an important step in fatty acid biosynthesis. 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). The active ingredient found in Nexletol is Bempedoic acid. : HY-16450 SB 204990 is a potent and specific inhibitor of ATP citrate lyase (ACLY) enzyme. novel bioactive compounds, analogs & targets. To date only partial X-ray structures of ACLY have been solved, thus limiting the design of novel inhibitors. Methods of inducing apoptosis in cancer cells using an ATP citrate lyase inhibitor and/or tricarboxylate transporter inhibitor are disclosed. It is an ATP Citrate Lyase (ACL) inhibitor. It catalyzes the formation of acetyl-CoA and oxaloacetate from citrate and CoA with a concomitant hydrolysis of ATP to ADP and phosphate. The acetyl-CoA product is crucial for fatty acid metabolism, cholesterol biosynthesis, and post-translational modification of proteins (acetylation and prenylaion). 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. e. Hyperuricemia and increased risk of tendon rupture or injury is reported side effect of the drug. 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.. [PubMed:22102020] Drug Relations Drug Relations 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. It is one of the major sources of cytosolic acetyl-CoA, and is a central metabolic enzyme. Chemical inhibitors such as BMS-303141 is a potent, cell-permeable ATP-citrate lyase (ACL) inhibitor with an IC50 value of 0.13 μM. Bempedoic Acid (ETC-1002): an Investigational Inhibitor of ATP Citrate Lyase. It can inhibit the growth and progression of prostate cancer cells and play a corresponding inhibitory effect in animal models. 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. Title:ATP Citrate Lyase Inhibitors as Novel Cancer Therapeutic Agents. Objective: Bempedoic acid (BemA; ETC-1002) is a novel drug that targets hepatic ATP-citrate lyase to reduce cholesterol biosynthesis. 1 Inhibition of ATP citrate lyase … Sun T, Hayakawa K, Fraser ME: ADP-Mg2+ bound to the ATP-grasp domain of ATP-citrate lyase. 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. ATP-citrate lyase (ACLY) is an enzyme that links glycolysis to lipid metabolism. d. The recommended dose should be taken every 8 hours. ATP-citrate lyase (ACLY) catalyzes the ATP-dependent conversion of citrate and CoA to oxaloacetate and acetyl-CoA. To investigate the effect of ACLY inhibition on lipid metabolism, metabolome and transcriptome analysis was performed. Epub 2011 Sep 24. 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. 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. NDI-091143 inhibits ACLY catalysis allosterically, by stabilizing large conformational changes in the citrate domain that indirectly block the binding and recognition of citrate. Curr Atheroscler Rep. 2016; 18(10):61 (ISSN: 1534-6242) Bilen O; Ballantyne CM. 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. 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. ATP citrate lyase inhibitors as novel cancer therapeutic agents. Acta Crystallogr Sect F Struct Biol Cryst Commun. Synonyms: ETC1002, ETC 1002, Bempedoic acid, ESP-55016. BMS-303141 shows inhibition of total lipid syntheses with IC50 of 8 μM in HepG2 cells. ATP citrate lyase (ACL) catalyzes an ATP-dependent biosynthetic reaction which produces acetyl-coenzyme A and oxaloacetate from citrate and coenzyme A (CoA). A role for ATP Citrate Lyase in cell cycle regulation during myeloid differentiation. What’s more, small interfering RNAs have been used to down-regulate the expression of ATP citrate lyase. 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. 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. Rhee J(1), Solomon LA(1), DeKoter RP(2). 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