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Biochemical and structural evaluation of highly selective 2-arylbenzoxazole-based transthyretin amyloidogenesis inhibitors.

Johnson SM, Connelly S, Wilson IA, Kelly JW
J Med Chem 51 260-70 (2008)
Related entries: 2qgc, 2qgd, 2qge

Cited: 58 times
EuropePMC logo PMID: 18095641

Abstract

To develop potent transthyretin (TTR) amyloidogenesis inhibitors that also display high binding selectivity in blood, it proves useful to systematically optimize each of the three substructural elements that comprise a typical inhibitor: the two aryl rings and the linker joining them. In the first study, described herein, structural modifications to one aryl ring were evaluated by screening a library of 2-arylbenzoxazoles bearing thyroid hormone-like aryl substituents on the 2-aryl ring. Several potent and highly selective amyloidogenesis inhibitors were identified that exhibit minimal thyroid hormone nuclear receptor and COX-1 binding. High resolution crystal structures (1.3-1.5 A) of three inhibitors (2f, 4f, and 4d) in complex with TTR were obtained to characterize their binding orientation. Collectively, the results demonstrate that thyroid hormone-like substitution patterns on one aryl ring lead to potent and highly selective TTR amyloidogenesis inhibitors that lack undesirable thyroid hormone receptor or COX-1 binding.

Reviews - 2qgb mentioned but not cited (2)

  1. Structure-based design of kinetic stabilizers that ameliorate the transthyretin amyloidoses. Connelly S, Choi S, Johnson SM, Kelly JW, Wilson IA. Curr Opin Struct Biol 20 54-62 (2010)
  2. Transthyretin Misfolding, A Fatal Structural Pathogenesis Mechanism. Si JB, Kim B, Kim JH. Int J Mol Sci 22 4429 (2021)

Articles - 2qgb mentioned but not cited (3)

  1. Potentially amyloidogenic conformational intermediates populate the unfolding landscape of transthyretin: insights from molecular dynamics simulations. Rodrigues JR, Simões CJ, Silva CG, Brito RM. Protein Sci 19 202-219 (2010)
  2. Evaluating the effect of mutations and ligand binding on transthyretin homotetramer dynamics. Saldaño TE, Zanotti G, Parisi G, Fernandez-Alberti S. PLoS One 12 e0181019 (2017)
  3. Stilbene Boronic Acids Form a Covalent Bond with Human Transthyretin and Inhibit Its Aggregation. Smith TP, Windsor IW, Forest KT, Raines RT. J Med Chem 60 7820-7834 (2017)


Reviews citing this publication (12)

  1. The transthyretin amyloidoses: from delineating the molecular mechanism of aggregation linked to pathology to a regulatory-agency-approved drug. Johnson SM, Connelly S, Fearns C, Powers ET, Kelly JW. J Mol Biol 421 185-203 (2012)
  2. Halogen bonding (X-bonding): a biological perspective. Scholfield MR, Zanden CM, Carter M, Ho PS. Protein Sci 22 139-152 (2013)
  3. Transthyretin: the servant of many masters. Buxbaum JN, Reixach N. Cell Mol Life Sci 66 3095-3101 (2009)
  4. Chemical and biological approaches for adapting proteostasis to ameliorate protein misfolding and aggregation diseases: progress and prognosis. Lindquist SL, Kelly JW. Cold Spring Harb Perspect Biol 3 a004507 (2011)
  5. Stabilization of protein-protein interactions in drug discovery. Andrei SA, Sijbesma E, Hann M, Davis J, O'Mahony G, Perry MWD, Karawajczyk A, Eickhoff J, Brunsveld L, Doveston RG, Milroy LG, Ottmann C. Expert Opin Drug Discov 12 925-940 (2017)
  6. Targeting intracellular and extracellular alpha-synuclein as a therapeutic strategy in Parkinson's disease and other synucleinopathies. Vekrellis K, Stefanis L. Expert Opin Ther Targets 16 421-432 (2012)
  7. Current and future treatment of amyloid diseases. Ankarcrona M, Winblad B, Monteiro C, Fearns C, Powers ET, Johansson J, Westermark GT, Presto J, Ericzon BG, Kelly JW. J Intern Med 280 177-202 (2016)
  8. An overview of drugs currently under investigation for the treatment of transthyretin-related hereditary amyloidosis. Obici L, Merlini G. Expert Opin Investig Drugs 23 1239-1251 (2014)
  9. Functional Amyloid Signaling via the Inflammasome, Necrosome, and Signalosome: New Therapeutic Targets in Heart Failure. Parry TL, Melehani JH, Ranek MJ, Willis MS. Front Cardiovasc Med 2 25 (2015)
  10. Uncovering the Neuroprotective Mechanisms of Curcumin on Transthyretin Amyloidosis. Ferreira N, Saraiva MJ, Almeida MR. Int J Mol Sci 20 E1287 (2019)
  11. A current pharmacologic agent versus the promise of next generation therapeutics to ameliorate protein misfolding and/or aggregation diseases. Baranczak A, Kelly JW. Curr Opin Chem Biol 32 10-21 (2016)
  12. Review on the Structures and Activities of Transthyretin Amyloidogenesis Inhibitors. Guo X, Liu Z, Zheng Y, Li Y, Li L, Liu H, Chen Z, Wu L. Drug Des Devel Ther 14 1057-1081 (2020)

Articles citing this publication (41)

  1. Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade. Bulawa CE, Connelly S, Devit M, Wang L, Weigel C, Fleming JA, Packman J, Powers ET, Wiseman RL, Foss TR, Wilson IA, Kelly JW, Labaudinière R. Proc Natl Acad Sci U S A 109 9629-9634 (2012)
  2. Quantification of the thermodynamically linked quaternary and tertiary structural stabilities of transthyretin and its disease-associated variants: the relationship between stability and amyloidosis. Hurshman Babbes AR, Powers ET, Kelly JW. Biochemistry 47 6969-6984 (2008)
  3. Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity. Sant'Anna R, Gallego P, Robinson LZ, Pereira-Henriques A, Ferreira N, Pinheiro F, Esperante S, Pallares I, Huertas O, Almeida MR, Reixach N, Insa R, Velazquez-Campoy A, Reverter D, Reig N, Ventura S. Nat Commun 7 10787 (2016)
  4. Aromatic sulfonyl fluorides covalently kinetically stabilize transthyretin to prevent amyloidogenesis while affording a fluorescent conjugate. Grimster NP, Connelly S, Baranczak A, Dong J, Krasnova LB, Sharpless KB, Powers ET, Wilson IA, Kelly JW. J Am Chem Soc 135 5656-5668 (2013)
  5. Toward optimization of the linker substructure common to transthyretin amyloidogenesis inhibitors using biochemical and structural studies. Johnson SM, Connelly S, Wilson IA, Kelly JW. J Med Chem 51 6348-6358 (2008)
  6. Chemoselective small molecules that covalently modify one lysine in a non-enzyme protein in plasma. Choi S, Connelly S, Reixach N, Wilson IA, Kelly JW. Nat Chem Biol 6 133-139 (2010)
  7. The heat shock response modulates transthyretin deposition in the peripheral and autonomic nervous systems. Santos SD, Fernandes R, Saraiva MJ. Neurobiol Aging 31 280-289 (2010)
  8. A substructure combination strategy to create potent and selective transthyretin kinetic stabilizers that prevent amyloidogenesis and cytotoxicity. Choi S, Reixach N, Connelly S, Johnson SM, Wilson IA, Kelly JW. J Am Chem Soc 132 1359-1370 (2010)
  9. Toward optimization of the second aryl substructure common to transthyretin amyloidogenesis inhibitors using biochemical and structural studies. Johnson SM, Connelly S, Wilson IA, Kelly JW. J Med Chem 52 1115-1125 (2009)
  10. Trapping of palindromic ligands within native transthyretin prevents amyloid formation. Kolstoe SE, Mangione PP, Bellotti V, Taylor GW, Tennent GA, Deroo S, Morrison AJ, Cobb AJ, Coyne A, McCammon MG, Warner TD, Mitchell J, Gill R, Smith MD, Ley SV, Robinson CV, Wood SP, Pepys MB. Proc Natl Acad Sci U S A 107 20483-20488 (2010)
  11. How much binding affinity can be gained by filling a cavity? Kawasaki Y, Chufan EE, Lafont V, Hidaka K, Kiso Y, Mario Amzel L, Freire E. Chem Biol Drug Des 75 143-151 (2010)
  12. A stilbene that binds selectively to transthyretin in cells and remains dark until it undergoes a chemoselective reaction to create a bright blue fluorescent conjugate. Choi S, Ong DS, Kelly JW. J Am Chem Soc 132 16043-16051 (2010)
  13. Iodine atoms: a new molecular feature for the design of potent transthyretin fibrillogenesis inhibitors. Mairal T, Nieto J, Pinto M, Almeida MR, Gales L, Ballesteros A, Barluenga J, Pérez JJ, Vázquez JT, Centeno NB, Saraiva MJ, Damas AM, Planas A, Arsequell G, Valencia G. PLoS One 4 e4124 (2009)
  14. A competition assay to identify amyloidogenesis inhibitors by monitoring the fluorescence emitted by the covalent attachment of a stilbene derivative to transthyretin. Choi S, Kelly JW. Bioorg Med Chem 19 1505-1514 (2011)
  15. Structurally simple inhibitors of lanosterol 14alpha-demethylase are efficacious in a rodent model of acute Chagas disease. Suryadevara PK, Olepu S, Lockman JW, Ohkanda J, Karimi M, Verlinde CL, Kraus JM, Schoepe J, Van Voorhis WC, Hamilton AD, Buckner FS, Gelb MH. J Med Chem 52 3703-3715 (2009)
  16. Identification of a novel ligand binding motif in the transthyretin channel. Lima LM, Silva Vde A, Palmieri Lde C, Oliveira MC, Foguel D, Polikarpov I. Bioorg Med Chem 18 100-110 (2010)
  17. Stilbene vinyl sulfonamides as fluorogenic sensors of and traceless covalent kinetic stabilizers of transthyretin that prevent amyloidogenesis. Suh EH, Liu Y, Connelly S, Genereux JC, Wilson IA, Kelly JW. J Am Chem Soc 135 17869-17880 (2013)
  18. A one-pot hypoiodite catalysed oxidative cycloetherification approach to benzoxazoles. Boominathan SS, Hu WP, Senadi GC, Vandavasi JK, Wang JJ. Chem Commun (Camb) 50 6726-6728 (2014)
  19. Sulfonamido-2-arylbenzoxazole GroEL/ES Inhibitors as Potent Antibacterials against Methicillin-Resistant Staphylococcus aureus (MRSA). Abdeen S, Kunkle T, Salim N, Ray AM, Mammadova N, Summers C, Stevens M, Ambrose AJ, Park Y, Schultz PG, Horwich AL, Hoang QQ, Chapman E, Johnson SM. J Med Chem 61 7345-7357 (2018)
  20. Tafamidis (Vyndaqel): a light for FAP patients. Nencetti S, Rossello A, Orlandini E. ChemMedChem 8 1617-1619 (2013)
  21. A novel strategy for the construction of substituted benzoxazoles via a tandem oxidative process. Gu L, Jin C, Guo J, Zhang L, Wang W. Chem Commun (Camb) 49 10968-10970 (2013)
  22. Chlorination and ortho-acetoxylation of 2-arylbenzoxazoles. Leng Y, Yang F, Zhu W, Wu Y, Li X. Org Biomol Chem 9 5288-5296 (2011)
  23. The putative role of some conserved water molecules in the structure and function of human transthyretin. Banerjee A, Dasgupta S, Mukhopadhyay BP, Sekar K. Acta Crystallogr D Biol Crystallogr 71 2248-2266 (2015)
  24. Bifunctional coumarin derivatives that inhibit transthyretin amyloidogenesis and serve as fluorescent transthyretin folding sensors. Myung N, Connelly S, Kim B, Park SJ, Wilson IA, Kelly JW, Choi S. Chem Commun (Camb) 49 9188-9190 (2013)
  25. Pseudomonas aeruginosa porphobilinogen synthase assembly state regulators: hit discovery and initial SAR studies. Reitz AB, Ramirez UD, Stith L, Du Y, Smith GR, Jaffe EK. ARKIVOC 2010 175-188 (2010)
  26. Synthesis and structure-activity relationships of novel fused ring analogues of Q203 as antitubercular agents. Kang S, Kim YM, Jeon H, Park S, Seo MJ, Lee S, Park D, Nam J, Lee S, Nam K, Kim S, Kim J. Eur J Med Chem 136 420-427 (2017)
  27. Conserved water mediated H-bonding dynamics of Ser117 and Thr119 residues in human transthyretin-thyroxin complexation: inhibitor modeling study through docking and molecular dynamics simulation. Banerjee A, Bairagya HR, Mukhopadhyay BP, Nandi TK, Mishra DK. J Mol Graph Model 44 70-80 (2013)
  28. Semi-quantitative models for identifying potent and selective transthyretin amyloidogenesis inhibitors. Connelly S, Mortenson DE, Choi S, Wilson IA, Powers ET, Kelly JW, Johnson SM. Bioorg Med Chem Lett 27 3441-3449 (2017)
  29. Understanding the microscopic binding mechanism of hydroxylated and sulfated polybrominated diphenyl ethers with transthyretin by molecular docking, molecular dynamics simulations and binding free energy calculations. Cao H, Sun Y, Wang L, Zhao C, Fu J, Zhang A. Mol Biosyst 13 736-749 (2017)
  30. Development of transgenic Caenorhabditis elegans expressing human transthyretin as a model for drug screening. Tsuda Y, Yamanaka K, Toyoshima R, Ueda M, Masuda T, Misumi Y, Ogura T, Ando Y. Sci Rep 8 17884 (2018)
  31. An insight to the conserved water mediated dynamics of catalytic His88 and its recognition to thyroxin and RBP binding residues in human transthyretin. Banerjee A, Mukhopadhyay BP. J Biomol Struct Dyn 33 1973-1988 (2015)
  32. Fluorogenic small molecules requiring reaction with a specific protein to create a fluorescent conjugate for biological imaging--what we know and what we need to learn. Baranczak A, Connelly S, Liu Y, Choi S, Grimster NP, Powers ET, Wilson IA, Kelly JW. Biopolymers 101 484-495 (2014)
  33. Systemic optimization and structural evaluation of quinoline derivatives as transthyretin amyloidogenesis inhibitors. Kim B, Park H, Lee SK, Park SJ, Koo TS, Kang NS, Hong KB, Choi S. Eur J Med Chem 123 777-787 (2016)
  34. A molecular basis for tetramer destabilization and aggregation of transthyretin Ala97Ser. Wang YS, Huang CH, Liou GG, Hsueh HW, Liang CT, Tseng HC, Huang SJ, Chao CC, Hsieh ST, Tzeng SR. Protein Sci 32 e4610 (2023)
  35. S8 -Mediated Cyclization of 2-Aminophenols/thiophenols with Arylmethyl Chloride: Approach to Benzoxazoles and Benzothiazoles. Gan H, Miao D, Pan Q, Hu R, Li X, Han S. Chem Asian J 11 1770-1774 (2016)
  36. Synthesis, molecular structure, DNA-binding, cytotoxicity, apoptosis and antioxidant activity of compounds containing aryloxazole. Wang XZ, Jiang GB, Lin GJ, Huang HL, Xie YY, Liu YJ. Eur J Med Chem 80 192-200 (2014)
  37. The biochemistry of disease: desperately seeking syzygy. Kozarich JW. Annu Rev Biochem 78 55-63 (2009)
  38. A green approach for the synthesis of 2-substituted benzoxazoles and benzothiazoles via coupling/cyclization reactions. Nguyen HT, Nguyen TH, Pham DD, Nguyen CT, Tran PH. Heliyon 7 e08309 (2021)
  39. Compound 275# Induces Mitochondria-Mediated Apoptosis and Autophagy Initiation in Colorectal Cancer Cells through an Accumulation of Intracellular ROS. Yang DL, Li Y, Ma SQ, Zhang YJ, Huang JH, He LJ. Molecules 28 3211 (2023)
  40. Efficient Cu-catalyzed intramolecular O-arylation for synthesis of benzoxazoles in water. Tang Y, Li M, Gao H, Rao G, Mao Z. RSC Adv 10 14317-14321 (2020)
  41. Enantioselective rhodium-catalyzed addition of arylboronic acids to N-heteroaryl ketones: synthesis of α-hydroxy acids. Zhu J, Li Z, Li J, Tian D, Xu R, Tan Z, Chen Z, Tang W. Chem Sci 14 1606-1612 (2023)


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