SREBP inhibitors: an updated patent review for 2008-present

References

• Shimano H, Sato R. SREBP-regulated lipid metabolism: convergent physiology — divergent pathophysiology. Nat Rev Endocrinol. 2017;13(12):710–30. doi: 10.1038/nrendo.2017.91
   PubMed Web of Science ®Google Scholar
• Tang JJ, Li JG, Qi W, et al. Inhibition of SREBP by a small molecule, betulin, improves hyperlipidemia and insulin resistance and reduces atherosclerotic plaques. Cell Metab. 2011;13(1):44–56. doi: 10.1016/j.cmet.2010.12.004
   PubMed Web of Science ®Google Scholar
• Debose-Boyd RA, Ye J. SREBPs in lipid metabolism, insulin signaling, and beyond. Trends Biochem Sci. 2018;43(5):358–368. doi: 10.1016/j.tibs.2018.01.005
   PubMed Web of Science ®Google Scholar
• Horton JD, Goldstein JL, Brown MS. Srebps: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Investig. 2002;109(9):1125–1131. doi: 10.1172/JCI0215593
   PubMed Web of Science ®Google Scholar
• Brown MS, Goldstein JL. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell. 1997;89(3):331–340. doi: 10.1016/S0092-8674(00)80213-5
   PubMed Web of Science ®Google Scholar
• Shao W, Espenshade PJ. Expanding roles for SREBP in metabolism. Cell Metab. 2012;16(4):414–419. doi: 10.1016/j.cmet.2012.09.002
   PubMed Web of Science ®Google Scholar
• Dorotea D, Koya D, Ha H. Recent insights into SREBP as a direct mediator of kidney fibrosis via lipid-independent pathways. Front Pharmacol. 2020;11:265. doi: 10.3389/fphar.2020.00265
   PubMed Web of Science ®Google Scholar
• Repa JJ, Liang G, Ou J, et al. Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta. Genes Dev. 2000;14(22):2819–30. doi: 10.1101/gad.844900
   PubMed Web of Science ®Google Scholar
• Beltowski J. Liver X receptors (LXR) as therapeutic targets in dyslipidemia. Cardiovasc Ther. 2008;26(4):297–316. doi: 10.1111/j.1755-5922.2008.00062.x
   PubMed Web of Science ®Google Scholar
• Yellaturu CR, Deng X, Cagen LM, et al. Insulin enhances post-translational processing of nascent SREBP-1c by promoting its phosphorylation and association with COPII vesicles. J Biol Chem. 2009;284(12):7518–7532. doi: 10.1074/jbc.M805746200
   PubMed Web of Science ®Google Scholar
• Nohturfft A, Yabe D, Goldstein JL, et al. Regulated step in cholesterol feedback localized to budding of SCAP from ER membranes. Cell. 2000;102(3):315–323. doi: 10.1016/S0092-8674(00)00037-4
   PubMed Web of Science ®Google Scholar
• Debose-Boyd RA, Brown MS, Li WP, et al. Transport-dependent proteolysis of SREBP relocation of site-1 protease from Golgi to ER obviates the need for SREBP transport to Golgi. Cell. 1999;99(7):703–712. doi: 10.1016/S0092-8674(00)81668-2
   PubMed Web of Science ®Google Scholar
• Sakai J, Rawson RB, Espenshade PJ, et al. Molecular identification of the sterol-regulated luminal protease that cleaves SREBPs and controls lipid composition of animal cells. Mol Cell. 1998;2(4):505–514. doi: 10.1016/S1097-2765(00)80150-1
   PubMed Web of Science ®Google Scholar
• Rawson RB, Zelenski NG, Nijhawan D, et al. Complementation cloning of S2P, a gene encoding a putative metalloprotease required for intramembrane cleavage of SREBPs. Mol Cell. 1997;1(1):47–57. doi: 10.1016/S1097-2765(00)80006-4
   PubMed Web of Science ®Google Scholar
• Rawson RB. The SREBP pathway - insights from insigs and insects. Nat Rev Mol Cell Bio. 2003;4(8):631–40. doi: 10.1038/nrm1174
   PubMed Web of Science ®Google Scholar
• Düvel K, Yecies JL, Menon S, et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol Cell. 2010;39(2):171–183. doi: 10.1016/j.molcel.2010.06.022
   PubMed Web of Science ®Google Scholar
• Peterson TR, Sengupta SS, Harris TE, et al. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell. 2011;146(3):408–420. doi: 10.1016/j.cell.2011.06.034
   PubMed Web of Science ®Google Scholar
• Han Y, Hu Z, Cui A, et al. Post-translational regulation of lipogenesis via AMPK-dependent phosphorylation of insulin-induced gene. Nat Commun. 2019;10(1):623. doi: 10.1038/s41467-019-08585-4
   PubMedGoogle Scholar
• Porstmann T, Santos CR, Griffiths B, et al. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab. 2008;8(3):224–236. doi: 10.1016/j.cmet.2008.07.007
   PubMed Web of Science ®Google Scholar
• Yokoyama C, Wang X, Briggs MR, et al. SREBP-1, a basic-helix-loop-helix-leucine zipper protein that controls transcription of the low density lipoprotein receptor gene. Cell. 1993;75(1):187–197. doi: 10.1016/S0092-8674(05)80095-9
   PubMed Web of Science ®Google Scholar
• Sozen E, Demirel-Yalciner T, Sari D, et al. Deficiency of SREBP1c modulates autophagy mediated lipid droplet catabolism during oleic acid induced steatosis. Metabol Open. 2021;12:100138. doi: 10.1016/j.metop.2021.100138
   PubMedGoogle Scholar
• Sajan MP, Lee MC, Foufelle F, et al. Coordinated regulation of hepatic FoxO1, PGC-1α and SREBP-1c facilitates insulin action and resistance. Cell Signal. 2018;43:62–70. doi: 10.1016/j.cellsig.2017.12.005
   PubMed Web of Science ®Google Scholar
• Snaebjornsson MT, Janaki-Raman S, Schulze A. Greasing the wheels of the cancer machine: the role of lipid metabolism in cancer. Cell Metab. 2020;31(1):62–76. doi: 10.1016/j.cmet.2019.11.010
   PubMed Web of Science ®Google Scholar
• Cheng C, Geng F, Cheng X, et al. Lipid metabolism reprogramming and its potential targets in cancer. Cancer Commun (Lond). 2018;38(1):27. doi: 10.1186/s40880-018-0301-4
   PubMedGoogle Scholar
• Icard P, Wu Z, Fournel L, et al. ATP citrate lyase: A central metabolic enzyme in cancer. Cancer Lett. 2020;471:125–134. doi: 10.1016/j.canlet.2019.12.010
   PubMed Web of Science ®Google Scholar
• Fhu CW, Ali A. Fatty acid synthase: an emerging target in cancer. Molecules. 2020;25(17):3935. doi: 10.3390/molecules25173935
   PubMed Web of Science ®Google Scholar
• Wang C, Ma J, Zhang N, et al. The acetyl-CoA carboxylase enzyme: a target for cancer therapy? Expert Rev Anticancer Ther. 2015;15(6):667–676. doi: 10.1586/14737140.2015.1038246
   PubMed Web of Science ®Google Scholar
• Choi Y, Kawazoe Y, Murakami K, et al. Identification of bioactive molecules by adipogenesis profiling of organic compounds. J Biol Chem. 2003;278(9):7320–7324. doi: 10.1074/jbc.M210283200
   PubMed Web of Science ®Google Scholar
• Kamisuki S, Mao Q, Abu-Elheiga L, et al. A small molecule that blocks fat synthesis by inhibiting the activation of SREBP. Chem Biol. 2009;16(8):882–892. doi: 10.1016/j.chembiol.2009.07.007
   PubMedGoogle Scholar
• Shao W, Machamer CE, Espenshade PJ. Fatostatin blocks ER exit of SCAP but inhibits cell growth in a SCAP-independent manner. J Lipid Res. 2016;57(8):1564–1573. doi: 10.1194/jlr.M069583
   PubMed Web of Science ®Google Scholar
• Gholkar AA, Cheung K, Williams KJ, et al. Fatostatin inhibits cancer cell proliferation by affecting mitotic microtubule spindle assembly and cell division. J Biol Chem. 2016;291(33):17001–17008. doi: 10.1074/jbc.C116.737346
   PubMed Web of Science ®Google Scholar
• Freed-Pastor WA, Prives C, Osborne T Use of Fatostatin for treating cancer having a p53 mutation. US2014364460. 2014 12 11.
   Google Scholar
• Uesugi M, Wakil SJ, Abu-Elheiga L, et al. Compositions and methods for the treatment of metabolic disorders. WO2008097835. 2008 08 14.
   Google Scholar
• Kamisuki S, Shirakawa T, Kugimiya A, et al. Synthesis and evaluation of diarylthiazole derivatives that inhibit activation of sterol regulatory element-binding proteins. J Med Chem. 2011;54(13):4923–4927. doi: 10.1021/jm200304y
   PubMed Web of Science ®Google Scholar
• Bernales S, Lindquist J, Guha M. Srebp blockers for use in treating liver fibrosis, elevated cholesterol and insulin resistance. WO2016141159. 2016 Sep 09.
   Google Scholar
• Pujala B, Jangir R, Guguloth R, et al. Sterol regulatory element-binding proteins (SREBPS) Inhibitors. WO2016141258. 2016 Sep 09.
   Google Scholar
• Huff J, Uesugi M, Kincaid J Di-substituted pyrazole compounds for treatment of diseases. WO2017190086. 2017 Nov 2.
   Google Scholar
• Green MJ, Har BP. Srebp inhibitors comprising a 6-membered central ring. WO2019148125. 2019 Aug 01.
   Google Scholar
• Green MJ, Hart BP. Srebp inhibitor comprising a thiophene central ring. WO2021097122. 2021 May 20.
   Google Scholar
• Green MJ, Hart B Srebp inhibitors comprising a thiophene central ring. WO2022020738. 2022 Jan 27.
   Google Scholar
• Wang CG, Zhou J Compositions and methods for treating cancer with aberrant lipogenic signaling. WO2014004054. 2015 01 22.
   Google Scholar
• Malik S, Roeder RG. The metazoan mediator co-activator complex as an integrative hub for transcriptional regulation. Nat Rev Genet. 2010;11(11):761–772. doi: 10.1038/nrg2901
   PubMed Web of Science ®Google Scholar
• Li X, Yang FJ. Mediating lipid biosynthesis: implications for cardiovascular disease. Trends Cardiovasc Med. 2013;23(7):269–273. doi: 10.1016/j.tcm.2013.03.002
   PubMed Web of Science ®Google Scholar
• Yang F, Vought BW, Satterlee JS, et al. An ARC/Mediator subunit required for SREBP control of cholesterol and lipid homeostasis. Nature. 2006;442(7103):700–704. doi: 10.1038/nature04942
   PubMed Web of Science ®Google Scholar
• Zhao XP, Li X, Zong HH, et al. Inhibition of SREBP transcriptional activity by a boron-containing compound improves lipid homeostasis in diet-induced obesity. Diabetes. 2014;63(7):2464–2473. doi: 10.2337/db13-0835
   PubMed Web of Science ®Google Scholar
• Li Y, Wang C, Chen L, et al. Sterol regulatory element binding protein and acidic nucleoplasm DNA binding protein-1 inhibitor, preparation method and application thereof. CN111333672. 2020 06 26.
   Google Scholar
• Taguchi M, Suzuki R, Mikami A Tricyclic compound. WO2006080439. 2006-Aug-3.
   Google Scholar
• Yuan SF, Chen FH, Zhu X, et al. Compositions and methods for broad-spectrum antiviral therapy. CN111886008. 2020-Nov 3.
   Google Scholar
• Párraga A, Bellsolell L, Ferré-D’amaré AR, et al. Co-crystal structure of sterol regulatory element binding protein 1a at 2.3 å resolution. Structure. 1998;6(5):661–72. doi: 10.1016/S0969-2126(98)00067-7
   PubMed Web of Science ®Google Scholar
• Debrabander J, Parada L Benzamide or benzamine compounds useful as anticancer agents for the treatment of human cancers. US10112948. 2018 Oct 30.
   Google Scholar
• Li J, Zhang J, Tang J, et al. Thioureathiophene-containing compound and application thereof. CN104130240. 2014 Nov 5.
   Google Scholar
• Yin F Compound for inhibiting SREBP-1 target point and application thereof. CN110437140. 2019 Nov 12.
   Google Scholar
• Park EJ, Kim YM, Kim HJ, et al. (S)YS-51, a novel isoquinoline alkaloid, attenuates obesity-associated non-alcoholic fatty liver disease in mice by suppressing lipogenesis, inflammation and coagulation. Eur J Pharmacol. 2016;788:200–209. doi: 10.1016/j.ejphar.2016.06.040
   PubMed Web of Science ®Google Scholar
• 장기철. The composition for preventing and treating metabolic diseases containing tetrahydroisoquinoline alkaloid YS-51S. KR20150014719. 2015 Jun 3.
   Google Scholar
• Kim SG, Ki SH, Hwang SH Pharmaceutical composition containing 1,2-dithiolthione derivative for preventing or treating disease caused by overexpression of lxr-alpha. US9370504. 2016-06-21.
   Google Scholar
• Hwahng SH, Ki SH, Bae EJ, et al. Role of adenosine monophosphate-activated protein kinase-p70 ribosomal S6 kinase-1 pathway in repression of liver X receptor-alpha-dependent lipogenic gene induction and hepatic steatosis by a novel class of dithiolethiones. Hepatology. 2009;49(6):1913–1925. doi: 10.1002/hep.22887
   PubMed Web of Science ®Google Scholar
• Kang KW, Kim YG, Cho MK, et al. Oltipraz regenerates cirrhotic liver through CCAAT/enhancer binding protein-mediated stellate cell inactivation. FASEB J. 2002;16(14):1988–1990. doi: 10.1096/fj.02-0406fje
   PubMedGoogle Scholar
• Jaen JC, Li L, Brown MS, et al. Modulators of SREBP processing. United States patent US 6,649,593. 2003 Nov 18.
   Google Scholar
• Hay BA, Abrams B, Zumbrunn AY, et al. Aminopyrrolidineamide inhibitors of site-1 protease. Bioorg Med Chem Lett. 2007;17(16):4411–4414. doi: 10.1016/j.bmcl.2007.06.031
   PubMed Web of Science ®Google Scholar
• Bai T, Yang Y, Yao YL, et al. Betulin alleviated ethanol-induced alcoholic liver injury via SIRT1/AMPK signaling pathway. Pharmacol Res. 2016;105:1–12. doi: 10.1016/j.phrs.2015.12.022
   PubMed Web of Science ®Google Scholar
• Gui YZ, Yan H, Gao F, et al. Betulin attenuates atherosclerosis in apoE(-/-) mice by up-regulating ABCA1 and ABCG1. Acta Pharmacol Sin. 2016;37(10):1337–48. doi: 10.1038/aps.2016.46
   PubMed Web of Science ®Google Scholar
• Quan HY, Kim DY, Kim SJ, et al. Betulinic acid alleviates non-alcoholic fatty liver by inhibiting SREBP1 activity via the AMPK-mTOR-SREBP signaling pathway. Biochem Pharmacol. 2013;85(9):1330–40. doi: 10.1016/j.bcp.2013.02.007
   PubMed Web of Science ®Google Scholar
• Wang Z, Liu Q, Ding L, et al. Rosin type diterpene derivative as well as preparation method and application thereof. CN104557823. 2015 Apr 29.
   Google Scholar
• Jeong HG, Hwang YP, Choi JH, et al. A composition comprising 3-caffeoyl-4-dihydrocaffeoylquinic acid for treating or preventing fatty liver or obesity. KR101448466. 2014 Oct 16.
   Google Scholar
• Shih CC, Kuo YH, Lin CH, et al. Method for treatment of hyperglycemia and hyperlipidemia. US10124012. 2018-Nov-13.
   Google Scholar
• Lee S, Lim HJ, Park JH, et al. Berberine-induced LDLR up-regulation involves JNK pathway. Biochem Biophys Res Commun. 2007;362(4):853–857. doi: 10.1016/j.bbrc.2007.08.060
   PubMed Web of Science ®Google Scholar
• Jiandong J, Weijia K, Lixun Z, et al. Method and composition for the treatment of hyperlipidemia. CN101102768. 2008 Jan 9.
   Google Scholar
• Li W, Yuan X, Rong X, et al. Poly-nuclear molecular compound and preparation method and application thereof. CN103709157. 2014 Apr 9.
   Google Scholar
• Korn BS, Shimomura I, Bashmakov Y, et al. Blunted feedback suppression of SREBP processing by dietary cholesterol in transgenic mice expressing sterol-resistant SCAP(D443N). J Clin Invest. 1998;102(12):2050–2060. doi: 10.1172/JCI5341
   PubMed Web of Science ®Google Scholar
• Ren S, Hylemon PB, Marques D, et al. Overexpression of cholesterol transporter StAR increases in vivo rates of bile acid synthesis in the rat and mouse. Hepatology. 2004;40(4):910–917. doi: 10.1002/hep.1840400421
   PubMed Web of Science ®Google Scholar
• Repa JJ, Mangelsdorf DJ. The role of orphan nuclear receptors in the regulation of cholesterol homeostasis. Annu Rev Cell Dev Biol. 2000;16(1):459–481. doi: 10.1146/annurev.cellbio.16.1.459
   PubMedGoogle Scholar
• Joseph SB, Mckilligin E, Pei L, et al. Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc Natl Acad Sci, USA. 2002;99(11):7604–7609. doi: 10.1073/pnas.112059299
   PubMed Web of Science ®Google Scholar
• Terasaka N, Hiroshima A, Koieyama T, et al. T-0901317, a synthetic liver X receptor ligand, inhibits development of atherosclerosis in LDL receptor-deficient mice. FEBS Lett. 2003;536(1–3):6–11. doi: 10.1016/S0014-5793(02)03578-0
   PubMed Web of Science ®Google Scholar
• Schultz JR, Tu H, Luk A, et al. Role of LXRs in control of lipogenesis. Genes Dev. 2000;14(22):2831–2838. doi: 10.1101/gad.850400
   PubMed Web of Science ®Google Scholar
• Ren S, Pandak WM Nuclear sulfated oxysterol, potent regulator of lipid homeostasis, for therapy of hypercholesterolemia, hypertriglycerides, fatty liver diseases, and atherosclerosis. US8399441. 2013 Mar 19.
   Google Scholar
• Horton JD, Shah NA, Warrington JA, et al. Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc Natl Acad Sci, USA. 2003;100(21):12027–12032. doi: 10.1073/pnas.1534923100
   PubMed Web of Science ®Google Scholar
• Halperin JA, Atkas H Methods and compositions for determining cholesterol-reducing properties of compounds. WO2009073252. 2009 Jun 11.
   Google Scholar
• Abumweis SS, Marinangeli CP, Frohlich J, et al. Implementing phytosterols into medical practice as a cholesterol-lowering strategy: overview of efficacy, effectiveness, and safety. Can J Cardiol. 2014;30(10):1225–32. doi: 10.1016/j.cjca.2014.04.022
   PubMed Web of Science ®Google Scholar
• Jiang SY, Yang X, Yang Z, et al. Discovery of an insulin-induced gene binding compound that ameliorates nonalcoholic steatohepatitis by inhibiting sterol regulatory element-binding protein-mediated lipogenesis. Hepatology. 2022;76(5):1466–81. doi: 10.1002/hep.32381
   PubMed Web of Science ®Google Scholar
• Rao YU, Song B, Yang X, et al. Application of compound in prevention and treatment of metabolic diseases. CN109833319. 2019 Jun 4.
   Google Scholar
• Kawagoe F, Mendoza A, Hayata Y, et al. Discovery of a vitamin D receptor-silent vitamin D derivative that impairs sterol regulatory element-binding protein in vivo. J Med Chem. 2021;64(9):5689–5709. doi: 10.1021/acs.jmedchem.0c02179
   PubMed Web of Science ®Google Scholar
• Asano L, Watanabe M, Ryoden Y, et al. Vitamin D metabolite, 25-Hydroxyvitamin D, regulates lipid metabolism by Inducing degradation of SREBP/SCAP. Cell Chem Biol. 2017;24(2):207–217. doi: 10.1016/j.chembiol.2016.12.017
   PubMed Web of Science ®Google Scholar
• Bhaswant M, Poudyal H, Brown L. Mechanisms of enhanced insulin secretion and sensitivity with n-3 unsaturated fatty acids. J Nutr Biochem. 2015;26(6):571–584. doi: 10.1016/j.jnutbio.2015.02.001
   PubMed Web of Science ®Google Scholar
• Zhang TT, Xu J, Wang YM, et al. Health benefits of dietary marine DHA/EPA-enriched glycerophospholipids. Prog Lipid Res. 2019;75:100997. doi: 10.1016/j.plipres.2019.100997
   PubMed Web of Science ®Google Scholar
• Jump DB, Botolin D, Wang Y, et al. Fatty acid regulation of hepatic gene transcription. J Nutr. 2005;135(11):2503–2506. doi: 10.1093/jn/135.11.2503
   PubMed Web of Science ®Google Scholar
• Liu X, Xue Y, Liu C, et al. Eicosapentaenoic acid-enriched phospholipid ameliorates insulin resistance and lipid metabolism in diet-induced-obese mice. Lipids Health Dis. 2013;12(1):109. doi: 10.1186/1476-511X-12-109
   PubMedGoogle Scholar
• Sekiya M, Yahagi N, Matsuzaka T, et al. Polyunsaturated fatty acids ameliorate hepatic steatosis in obese mice by SREBP-1 suppression. Hepatology. 2003;38(6):1529–1539. doi: 10.1016/j.hep.2003.09.028
   PubMed Web of Science ®Google Scholar
• Tanaka N, Zhang X, Sugiyama E, et al. Eicosapentaenoic acid improves hepatic steatosis independent of PPARα activation through inhibition of SREBP-1 maturation in mice. Biochem Pharmacol. 2010;80(10):1601–1612. doi: 10.1016/j.bcp.2010.07.031
   PubMed Web of Science ®Google Scholar
• Kogure R, Toyama K, Hiyamuta S, et al. 5-Hydroxy-eicosapentaenoic acid is an endogenous GPR119 agonist and enhances glucose-dependent insulin secretion. Biochem Biophys Res Commun. 2011;416(1–2):58–63. doi: 10.1016/j.bbrc.2011.10.141
   PubMed Web of Science ®Google Scholar
• Yang JW, Kim HS, Im JH, et al. GPR119: a promising target for nonalcoholic fatty liver disease. FASEB J. 2016;30(1):324–335. doi: 10.1096/fj.15-273771
   PubMed Web of Science ®Google Scholar
• Hu Y, Luo M, Guo J, et al. Hypolipidemic drug combination and application there of. CN105232525. 2016 01 13.
   Google Scholar
• Vu CB, Bemis JE, Benson E, et al. Synthesis and characterization of fatty acid conjugates of niacin and salicylic acid. J Med Chem. 2016;59(3):1217–1231. doi: 10.1021/acs.jmedchem.5b01961
   PubMed Web of Science ®Google Scholar
• Horton JD, Cohen JC, Hobbs HH. PCSK9: a convertase that coordinates LDL catabolism. J Lipid Res. 2009;50(Suppl):S172–7. doi: 10.1194/jlr.R800091-JLR200
   PubMed Web of Science ®Google Scholar
• Jirousek MR, Milne JC, Vu CB Fatty acid niacin conjugates. CN105916378. 2016 Aug 31.
   Google Scholar
• Saito H, Tachiura W, Nishimura M, et al. Hydroxylation site-specific and production-dependent effects of endogenous oxysterols on cholesterol homeostasis: implications for SREBP-2 and LXR. J Biol Chem. 2023;299(1):102733. doi: 10.1016/j.jbc.2022.102733
   PubMed Web of Science ®Google Scholar