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Review

Small molecules as activators in medicinal chemistry (2000–2016)

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Pages 1089-1110 | Received 07 Jan 2017, Accepted 26 Jun 2017, Published online: 06 Jul 2017

References

  • Darby JF, Landström J, Roth C, et al. Discovery of selective small molecule activators of a bacterial glycoside hydrolase. Angew Chem. 2014;126:13637–13641.
  • Hardie DG, Carling D, Gamblin SJ. AMP-activated protein kinase: also regulated by ADP? Trends Biochem Sci. 2011;36:470–477.
  • Towler MC, Hardie DG. AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res. 2007;100:328–341.
  • Viollet B, Mounier R, Leclerc J, et al. Targeting AMP-activated protein kinase as a novel therapeutic approach for the treatment of metabolic disorders. Diabetes Metab. 2007;33:395–402.
  • Cool B, Zinker B, Chiou W, et al. Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab. 2006;3:403–416.
  • Xiao B, Sanders MJ, Carmena D, et al. Structural basis of AMPK regulation by small molecule activators. Nat Commun. 2013;4.
  • Nakamura A, Terauchi Y. Present status of clinical deployment of glucokinase activators. J Diabetes Investig. 2015;6:124–132.
  • Matschinsky FM, Zelent B, Doliba NM, et al. Research and development of glucokinase activators for diabetes therapy: theoretical and practical aspects. Mathias Schwanstecher (Editor). In: Diabetes-perspectives in drug therapy. Berlin Heidelberg:Springer; 2011. p. 357–401.
  • Grimsby J, Sarabu R, Corbett WL, et al. Allosteric activators of glucokinase: potential role in diabetes therapy. Science. 2003;301:370–373.
  • Leighton B, Atkinson A, Coghlan M. Small molecule glucokinase activators as novel anti-diabetic agents. Biochem Soc Trans. 2005;33:371–374.
  • Pal M. Recent advances in glucokinase activators for the treatment of type 2 diabetes. Drug Discov Today. 2009;14:784–792.
  • Kamata K, Mitsuya M, Nishimura T, et al. Structural basis for allosteric regulation of the monomeric allosteric enzyme human glucokinase. Structure. 2004;12:429–438.
  • Hurley TD, Howard JE, Li T-K. The pharmacogenomics of alcoholism.” Pharmacogenomics: the search for individualized therapies. In: Licinio J, Wong ML, editors. Pharmacogenomics: the search for individualized therapies. Weinheim;Los Angeles, CA:Wiley-VCH; 2002. p. 417–441.
  • Perez-Miller S, Younus H, Vanam R, et al. Alda-1 is an agonist and chemical chaperone for the common human aldehyde dehydrogenase 2 variant. Nat Struct Mol Biol. 2010;17:159–164.
  • Dollé L, Gao B. Pharmacological chaperone therapies: can aldehyde dehydrogenase activator make us healthier? J Hepatol. 2015;62:1228–1230.
  • Zhong W, Zhang W, Li Q, et al. Pharmacological activation of aldehyde dehydrogenase 2 by Alda-1 reverses alcohol-induced hepatic steatosis and cell death in mice. J Hepatol. 2015;62:1375–1381.
  • Dali-Youcef N, Lagouge M, Froelich S, et al. Sirtuins: the ‘magnificent seven’, function, metabolism and longevity. Ann Med. 2007;39:335–345.
  • Michan S, Sinclair D. Sirtuins in mammals: insights into their biological function. Biochem J. 2007;404:1–13.
  • Araki T, Sasaki Y, Milbrandt J. Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Science. 2004;305:1010–1013.
  • Chen J, Zhou Y, Mueller-Steiner S, et al. SIRT1 protects against microglia-dependent amyloid-β toxicity through inhibiting NF-κB signaling. J Biol Chem. 2005;280:40364–40374.
  • Kim D, Nguyen MD, Dobbin MM, et al. SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer’s disease and amyotrophic lateral sclerosis. Embo J. 2007;26:3169–3179.
  • Herranz D, Serrano M. SIRT1: recent lessons from mouse models. Nat Rev Cancer. 2010;10:819–823.
  • Borra MT, Smith BC, Denu JM. Mechanism of human SIRT1 activation by resveratrol. J Biol Chem. 2005;280:17187–17195.
  • Wood JG, Rogina B, Lavu S, et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature. 2004;430:686–689.
  • Cantó C, Auwerx J. Targeting sirtuin 1 to improve metabolism: all you need is NAD+? Pharmacol Rev. 2012;64:166–187.
  • Reinhart AA, Oglesby-Sherrouse AG. Regulation of Pseudomonas aeruginosa virulence by distinct iron sources. Genes. 2016;7:126.
  • Jimenez PN, Koch G, Papaioannou E, et al. Role of PvdQ in Pseudomonas aeruginosa virulence under iron-limiting conditions. Microbiology. 2010;156:49–59.
  • Choby JE, Skaar EP. Heme synthesis and acquisition in bacterial pathogens. J Mol Biol. 2016;428(17):3408–3428.
  • Wakeman CA, Stauff DL, Zhang Y, et al. Differential activation of Staphylococcus aureus heme detoxification machinery by heme analogues. J Bacteriol. 2014;196:1335–1342.
  • Anzaldi LL, Skaar EP. Overcoming the heme paradox: heme toxicity and tolerance in bacterial pathogens. Infect Immun. 2010;78:4977–4989.
  • Skaar EP, Surdel M, Sulikowski GA, et al. Methods for use of small molecule activators of hem-y/protoporphyrinogen oxidase (ppo). Patent US20160213780. 2016.
  • Torres VJ, Stauff DL, Pishchany G, et al. A Staphylococcus aureus regulatory system that responds to host heme and modulates virulence. Cell Host Microbe. 2007;1:109–119.
  • Osada H, Yano T, Koshino H, et al. Enopeptin A, a novel depsipeptide antibiotic with anti-bacteriophage activity. J Antibiot. 1991;44:1463–1466.
  • Sarabia F, Chammaa S, Ruiz AS, et al. Chemistry and biology of cyclic depsipeptides of medicinal and biological interest. Curr Med Chem. 2004;11:1309–1332.
  • Conlon BP, Nakayasu ES, Fleck LE, et al. Activated ClpP kills persisters and eradicates a chronic biofilm infection. Nature. 2013;503:365–370.
  • Sello JK, Carney DW. Enopeptin analogs and methods of use there of. patent WO2016037072. 2016.
  • Seong IS, Kang MS, Choi MK, et al. The C-terminal tails of HslU ATPase act as a molecular switch for activation of HslV peptidase. J Biol Chem. 2002;277:25976–25982.
  • Ramachandran R, Hartmann C, Song HK, et al. Functional interactions of HslV (ClpQ) with the ATPase HslU (ClpY). Proc Natl Acad Sci USA. 2002;99:7396–7401.
  • Azim MK, Rashid Y, Khan KM. Small molecule activators of HsIV protease for development of novel antimicrobials. Patent US9119857. 2015.
  • Ofiate SA, Tsai SY, Tsai MJ, et al. Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science. 1995;270:24.
  • Voegel JJ, Heine M, Zechel C, et al. TIF2, a 160 kDa transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors. Embo J. 1996;15:3667.
  • Lonard DM, Kumar R, O’Malley BW. Minireview: the SRC family of coactivators: an entree to understanding a subset of polygenic diseases? Mol Endocrinol. 2010;24:279–285.
  • Walsh CA, Qin L, Tien JC-Y, et al. The function of steroid receptor coactivator-1 in normal tissues and cancer. Int J Biol Sci. 2012;8:470–485.
  • Lonard DM, Wang L, O’malley BW, et al. Small molecule stimulators of steroid receptor coactivator proteins and their use in the treatment of cancer. Patent WO2016109470. 2016.
  • Lonard DM, O’Malley BW. Molecular pathways: targeting steroid receptor coactivators in cancer. Clin Cancer Res. 2016;22:5403–5407.
  • Wang Y, Lonard DM, Yu Y, et al. Small molecule inhibition of the steroid receptor coactivators, SRC-3 and SRC-1. Mol Endocrinol. 2011;25:2041–2053.
  • Wheeler DL, Iida M, Dunn EF. The role of SRC in solid tumors. Oncologist. 2009;14:667–678.
  • Jiang B, Hu L, Cui Y, et al. P53 activator small molecules. Patent WO2015192343. 2015.
  • Demma M, Maxwell E, Ramos R, et al. SCH529074, a small molecule activator of mutant p53, which binds p53 DNA binding domain (DBD), restores growth-suppressive function to mutant p53 and interrupts HDM2-mediated ubiquitination of wild type p53. J Biol Chem. 2010;285:10198–10212.
  • Lain S, Hollick JJ, Campbell J, et al. Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator. Cancer Cell. 2008;13:454–463.
  • Wang H, Yan C. A small-molecule p53 activator induces apoptosis through inhibiting MDMX expression in breast cancer cells. Neoplasia. 2011;13:611IN6–9.
  • Ataide SLH, Dos Santos Maria Manuel Duque VM, Loucsa PNA, et al. Tryptophanol-derived oxazoloisoindolinones: small-molecule p53 activators. Patent WO2014207688. 2014.
  • Bockbrader KM, Tan M, Sun Y. A small molecule smac-mimic compound induces apoptosis and sensitizes TRAIL-and etoposide-induced apoptosis in breast cancer cells. Oncogene. 2005;24:7381–7388.
  • Fandy TE, Shankar S, Srivastava RK. Smac/DIABLO enhances the therapeutic potential of chemotherapeutic drugs and irradiation, and sensitizes TRAIL-resistant breast cancer cells. Mol Cancer. 2008;7:1.
  • Duckett CS. IAP proteins: sticking it to smac. Biochem J. 2005;385:E1.
  • Du C, Fang M, Li Y, et al. Smac, a mitochondrial protein that promotes cytochrome c–dependent caspase activation by eliminating IAP inhibition. Cell. 2000;102:33–42.
  • Hanson GJ, Thomas D, Chandrakumar N, et al. Small molecule apoptosis promoters. Patent US20120082640. 2012.
  • Moreno O, Natarajan S, Duncan DF. Small-molecule modulators of Trp-p8 activity. Patent US8618155. 2013.
  • MacDonald P, Wheeler M. Voltage-dependent K+ channels in pancreatic beta cells: role, regulation and potential as therapeutic targets. Diabetologia. 2003;46:1046–1062.
  • Nilius B, Droogmans G. Ion channels and their functional role in vascular endothelium. Physiol Rev. 2001;81:1415–1459.
  • Weaver CD. Compound, composition, and method of activating GIRK potassium channel and use of same for treating conditions of interest. Patent US9067894. 2015.
  • Nishizawa D, Gajya N, Ikeda K. Identification of selective agonists and antagonists to g protein-activated inwardly rectifying potassium channels: candidate medicines for drug dependence and pain. Curr Neuropharmacol. 2011;9:113–117.
  • Verkman AS, Namkung W. Small molecule activators of calcium-activated chloride channels and methods of use. Patent WO2013022793. 2013.
  • Arencibia JM, Pastor-Flores D, Bauer AF, et al. AGC protein kinases: from structural mechanism of regulation to allosteric drug development for the treatment of human diseases. Biochim Biophys Acta. 2013;1834:1302–1321.
  • Biondi RD, Engel MD. Use of a compound of formula I for making a pharmaceutical composition. Patent EP1486488. 2004.
  • Nagata S. Apoptosis by death factor. Cell. 1997;88:355–365.
  • Dudich E, Semenkova L, Gorbatova E, et al. Growth-regulative activity of human alpha-fetoprotein for different types of tumor and normal cells. Tumor Biol. 1997;19:30–40.
  • Buckley CD, Pilling D, Henriquez NV, et al. RGD peptides induce apoptosis by direct caspase-3 activation. Nature. 1999;397:534–539.
  • Dudich EI, Semenkova LN, Dudich IV, et al. Peptides modulating caspase activation. Patent WO2004033500. 2004.
  • Alom-Ruiz SP, Anilkumar N, Shah AM. Reactive oxygen species and endothelial activation. Antioxid Redox Signal. 2008;10:1089–1100.
  • Zampolli A, Basta G, Lazzerini G, et al. Inhibition of endothelial cell activation by nitric oxide donors. J Pharmacol Exp Ther. 2000;295:818–823.
  • Gluckman T, Grossman J, Folts J, et al. Regulation of leukocyte function by nitric oxide donors: the effect of S-nitroso-thiol complexes. J Toxicol Environ Health A. 2000;61:9–26.
  • Cruz D, Kwon O. Small Molecules For Endothelial Cell Activation. Patent US20130310417. 2013.
  • Tanzi RE, Bertram L. Twenty years of the Alzheimer’s disease amyloid hypothesis: a genetic perspective. Cell. 2005;120:545–555.
  • Vingtdeux V, Giliberto L, Zhao H, et al. AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-β peptide metabolism. J Biol Chem. 2010;285:9100–9113.
  • Salminen A, Kaarniranta K, Haapasalo A, et al. AMP‐activated protein kinase: a potential player in Alzheimer’s disease. J Neurochem. 2011;118:460–474.
  • Cai Z, Yan L-J, Li K, et al. Roles of AMP-activated protein kinase in Alzheimer’s disease. Neuromolecular Med. 2012;14:1–14.
  • Carling D, Sanders M, Woods A. The regulation of AMP-activated protein kinase by upstream kinases. Int J Obes. 2008;32:S55–S9.
  • Srivastava RAK, Pinkosky SL, Filippov S, et al. AMP-activated protein kinase: an emerging drug target to regulate imbalances in lipid and carbohydrate metabolism to treat cardio-metabolic diseases thematic review series: new lipid and lipoprotein targets for the treatment of cardiometabolic diseases. J Lipid Res. 2012;53:2490–2514.
  • Cameron KO, Kurumbail RG. Recent progress in the identification of adenosine monophosphate-activated protein kinase (ampk) activators. Bioorg Med Chem Lett. 2016;26:5139–5148.
  • Giordanetto F, Karis D. Direct AMP-activated protein kinase activators: a review of evidence from the patent literature. Expert Opin Ther Pat. 2012;22:1467–1477.
  • Cameron KO, Kung DW, Kalgutkar AS, et al. Discovery and preclinical characterization of 6-Chloro-5-[4-(1-hydroxycyclobutyl) phenyl]-1 H-indole-3-carboxylic Acid (PF-06409577), a direct activator of adenosine monophosphate-activated protein kinase (AMPK), for the potential treatment of diabetic nephropathy. J Med Chem. 2016;59:8068–8081.
  • Du -L-L, Chai D-M, Zhao L-N, et al. AMPK activation ameliorates Alzheimer’s disease-like pathology and spatial memory impairment in a streptozotocin-induced Alzheimer’s disease model in rats. J Alzheimers Dis. 2015;43:775–784.
  • Marambaud P, Vingtdeux V. Compounds and methods for prevention and treatment of alzheimer’s and other diseases. Patent WO2012027548. 2012.
  • Murakami Y, Matsufuji S, Kameji T, et al. Ornithine decarboxylase is degraded by the 26S proteasome without ubiquitination. Nature. 1992;360:597–599.
  • Burns MR, Graminski GF. Polyamine analogs that activate antizyme frameshifting. Patent US7144920. 2006.
  • Goodman M, Liu Z, Zhu P, et al. AMPK activators as a drug for diabetes, cancer and cardiovascular disease. Pharm Regul Aff. 2014;3(2):118.
  • Evans JM, Donnelly LA, Emslie-Smith AM, et al. Metformin and reduced risk of cancer in diabetic patients. Bmj. 2005;330:1304–1305.
  • Beck E, Scheen A. Anti-cancer activity of metformin: new perspectives for an old drug. Rev Med Suisse. 2010;6:1601–1607.
  • Bodmer M, Meier C, Krähenbühl S, et al. Long-term metformin use is associated with decreased risk of breast cancer. Diabetes Care. 2010;33:1304–1308.
  • Berstein LM, Boyarkina MP, Teslenko SY. Familial diabetes is associated with reduced risk of cancer in diabetic patients: a possible role for metformin. Med Oncol. 2012;29:1308–1313.

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