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.. The active ingredient found in Nexletol is Bempedoic acid. 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. The acetyl-CoA product is crucial for fatty acid metabolism, cholesterol biosynthesis, and post-translational modification of proteins (acetylation and prenylaion). ATP-citrate lyase (ACLY) catalyzes the ATP-dependent conversion of citrate and CoA to oxaloacetate and acetyl-CoA. J Cell Physiol 2012; 227: 1709 – 20. Synonyms: ETC1002, ETC 1002, Bempedoic acid, ESP-55016. Answer: (a, b, c, and e). 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. Objective: Bempedoic acid (BemA; ETC-1002) is a novel drug that targets hepatic ATP-citrate lyase to reduce cholesterol 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). Abstract ATP citrate lyase (ACLY), a key enzyme in the metabolic reprogramming of many cancers, is widely expressed in various mammalian tissues. ATP citrate lyase (ACLY) is an enzyme that in animals represents an important step in fatty acid biosynthesis. 2011 Oct 1;67(Pt 10):1168-72. doi: 10.1107/S1744309111028363. [PubMed:22102020] Drug Relations Drug Relations To date only partial X-ray structures of ACLY have been solved, thus limiting the design of novel inhibitors. The enzyme is a tetramer (relative molecular weight approximately 440,000) of apparently identical subunits. No. Emodin anthraquinones inhibited the enzymatic activity ATP-citrate lyase (ACL), a key player in cancer cell metabolism. Catalog No. Here, we demonstrate a novel function of the lipogenic enzyme, ATP citrate lyase (ACLY), in lipid metabolism in cancer cells. A role for ATP Citrate Lyase in cell cycle regulation during myeloid differentiation. To investigate the effect of ACLY inhibition on lipid metabolism, metabolome and transcriptome analysis was performed. Many tumors display a high rate of glucose utilization, as evidenced by 18-F-2-deoxyglucose PET imaging. : HY-16450 SB 204990 is a potent and specific inhibitor of ATP citrate lyase (ACLY) enzyme. ATP citrate lyase is an enzyme in the cholesterol–biosynthesis pathway located upstream of 3-hydroxy-3-methylglutaryl–coenzyme A reductase (HMGCR). NDI-091143 inhibits ACLY catalysis allosterically, by stabilizing large conformational changes in the citrate domain that indirectly block the binding and recognition of citrate. Recent Pat Anticancer Drug Discov. ATP citrate lyase (ACL) catalyzes an ATP-dependent biosynthetic reaction which produces acetyl-coenzyme A and oxaloacetate from citrate and coenzyme A (CoA). Keywords:ACL inhibitors, ATP … 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 (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. Curr Atheroscler Rep. 2016; 18(10):61 (ISSN: 1534-6242) Bilen O; Ballantyne CM. It catalyzes the formation of acetyl-CoA and oxaloacetate from citrate and CoA with a concomitant hydrolysis of ATP to ADP and phosphate. VOLUME: 7 ISSUE: 2. 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. ATP citrate lyase inhibitors as novel cancer therapeutic agents. Affiliation:Director, Human Health and Environment Program, Desert Research Institute Summerlin, 10530 Discovery Drive, Las Vegas, NV 89135, USA. d Purity: 99.72% Clinical Data:No Development Reported Size: 10 mM × 1 mL, 5 mg, 10 mg SB 204990 Cat. Sun T, Hayakawa K, Fraser ME: ADP-Mg2+ bound to the ATP-grasp domain of ATP-citrate lyase. ACLY depletion by small interfering RNAs caused growth suppression and/or apoptosis in a subset of cancer cell lines. Purity 99.94% Datasheet. 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. BMS-303141 shows inhibition of total lipid syntheses with IC50 of 8 μM in HepG2 cells. T3625 CAS 738606-46-7 . 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. Methods of treating individuals identified as having cancer using ATP citrate lyase inhibitor and/or tricarboxylate transporter inhibitor are disclosed. e. Hyperuricemia and increased risk of tendon rupture or injury is reported side effect of the drug. It is an ATP Citrate Lyase (ACL) inhibitor. 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. Recent Patents on Anti-Cancer Drug Discovery publishes review articles on recent patents in the field of anti-cancer drug discovery e.g. 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 can inhibit the growth and progression of prostate cancer cells and play a corresponding inhibitory effect in animal models. ATP-citrate lyase (ACLY) is an enzyme that links glycolysis to lipid metabolism. Epub 2011 Sep 24. 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 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. ATP-citrate lyase (ACL) is an extramitochondrial enzyme that is expressed in lipogenic tissues such as liver and adipose. Acta Crystallogr Sect F Struct Biol Cryst Commun. 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. Title:ATP Citrate Lyase Inhibitors as Novel Cancer Therapeutic Agents. 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. 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. Bempedoic acid is a prodrug.It is activated to the thioester with coenzyme A by the enzyme SLC27A2 in the liver. It is one of the major sources of cytosolic acetyl-CoA, and is a central metabolic enzyme. 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. 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. novel bioactive compounds, analogs & targets. • 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. BMS-303141 is a potent, cell-permeable inhibitor of ATP-citrate lyase (ACL) with IC50 of 0.13 μM. Summary: ATP citrate lyase is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues. Rhee J(1), Solomon LA(1), DeKoter RP(2). Bempedoic Acid (ETC-1002): an Investigational Inhibitor of ATP Citrate Lyase. 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