Positive allosteric modulation of the glucagon-like peptide-1 receptor by diverse electrophiles

Journal of Biological Chemistry

Volumn 291, Issue 20, 2016, Pages 10700-10715

  Bueno, Ana B ^a   Showalter, Aaron D ^b   Wainscott, David B ^b   Stutsman, Cynthia ^b   Marín, Aranzazu ^a   Ficorilli, James ^b   Cabrera, Over ^b   Willard, Francis S ^b   Sloop, Kyle W ^b  

^a ELI LILLY AND COMPANY   (Spain)

^b ELI LILLY AND COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMINO ACIDS; BINDING ENERGY; BINS; DIAGNOSIS; GLUCOSE; INSULIN; LIGANDS; MODULATORS; MOLECULES; PATIENT TREATMENT; PEPTIDES; PHYSIOLOGY;

ALLOSTERIC MODULATION; COVALENT MODIFICATIONS; GLUCAGON-LIKE PEPTIDE-1; HYDROGEN-DEUTERIUM EXCHANGE; POSITIVE ALLOSTERIC MODULATOR; SMALL MOLECULE ACTIVATION; THERAPEUTIC INTERVENTION; TYPE 2 DIABETES MELLITUS;

CELL SIGNALING;

4 (3 BENZYLOXYPHENYL) 2 ETHYLSULFINYL 6 (TRIFLUOROMETHYL)PYRIMIDINE; CYCLIC AMP; ELECTROPHILE; GLUCAGON LIKE PEPTIDE 1 RECEPTOR; GLUCAGON LIKE PEPTIDE 1 RECEPTOR AGONIST; UNCLASSIFIED DRUG; 4-(3-BENZYLOXYPHENYL)-2-ETHYLSULFANYL-6-(TRIFLUOROMETHYL)PYRIMIDINE; GLP1R PROTEIN, HUMAN; GLP1R PROTEIN, MOUSE; GLUCOSE; INSULIN; MUTANT PROTEIN; PYRIMIDINE DERIVATIVE;

ALLOSTERISM; ANIMAL CELL; ARTICLE; CONTROLLED STUDY; DRUG MECHANISM; DRUG STRUCTURE; FLUOROGRAPHY; IMMUNOPRECIPITATION; INSULIN RELEASE; LIQUID CHROMATOGRAPHY; MALE; MASS SPECTROMETRY; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN CONFORMATION; RECEPTOR UPREGULATION; SIGNAL TRANSDUCTION; AGONISTS; ANIMAL; C57BL MOUSE; CELL LINE; CHEMISTRY; DRUG EFFECTS; HEK293 CELL LINE; HUMAN; KNOCKOUT MOUSE; METABOLISM; PANCREAS ISLET; PANCREAS ISLET BETA CELL; RAT; SECRETION (PROCESS);

ALLOSTERIC REGULATION; ANIMALS; CELL LINE; CYCLIC AMP; GLUCAGON-LIKE PEPTIDE-1 RECEPTOR; GLUCOSE; HEK293 CELLS; HUMANS; INSULIN; INSULIN-SECRETING CELLS; ISLETS OF LANGERHANS; MALE; MICE; MICE, INBRED C57BL; MICE, KNOCKOUT; MUTANT PROTEINS; PYRIMIDINES; RATS; SIGNAL TRANSDUCTION;

EID: 84969277858     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.M115.696039     Document Type: Article

References (65)

1. Grauschopf, U., Lilie, H., Honold, K., Wozny, M., Reusch, D., Esswein, A., Schäfer, W., Rücknagel, K. P., and Rudolph, R. (2000) The N-terminal fragment of human parathyroid hormone receptor 1 constitutes a hormone binding domain and reveals a distinct disulfide pattern. Biochemistry 39, 8878-8887
2. Hofmann, B. A., Sydow, S., Jahn, O., van Werven, L., Liepold, T., Eckart, K., and Spiess, J. (2001) Functional and protein chemical characterization of the N-terminal domain of the rat corticotropin-releasing factor receptor 1. Protein Sci. 10, 2050-2062
3. Bazarsuren, A., Grauschopf, U., Wozny, M., Reusch, D., Hoffmann, E., Schaefer, W., Panzner, S., and Rudolph, R. (2002) In vitro folding, functional characterization, and disulfide pattern of the extracellular domain of human GLP-1 receptor. Biophys. Chem. 96, 305-318
4. Hoare, S. R. (2005) Mechanisms of peptide and nonpeptide ligand binding to class B G-protein-coupled receptors. Drug Discov. Today 10, 417-427
5. Parthier, C., Reedtz-Runge, S., Rudolph, R., and Stubbs, M. T. (2009) Passing the baton in class B GPCRs: peptide hormone activation via helix induction? Trends Biochem. Sci. 34, 303-310
6. Siu, F. Y., and Stevens, R. C. (2010) RAMP-ing up class-B GPCR ECD structural coverage. Structure 18, 1067-1068
7. Yang, L., Yang, D., de Graaf, C., Moeller, A., West, G. M., Dharmarajan, V., Wang, C., Siu, F. Y., Song, G., Reedtz-Runge, S., Pascal, B. D., Wu, B., Potter, C. S., Zhou, H., Griffin, P. R., et al. (2015) Conformational states of the full-length glucagon receptor. Nat. Commun. 6, 7859
8. Siu, F. Y., He, M., de Graaf, C., Han, G. W., Yang, D., Zhang, Z., Zhou, C., Xu, Q., Wacker, D., Joseph, J. S., Liu, W., Lau, J., Cherezov, V., Katritch, V., Wang, M. W., and Stevens, R. C. (2013) Structure of the human glucagon class B G-protein-coupled receptor. Nature 499, 444-449
9. Hollenstein, K., Kean, J., Bortolato, A., Cheng, R. K., Doré, A. S., Jazayeri, A., Cooke, R. M., Weir, M., and Marshall, F. H. (2013) Structure of class B GPCR corticotropin-releasing factor receptor 1. Nature 499, 438-443
10. Hollenstein, K., de Graaf, C., Bortolato, A., Wang, M. W., Marshall, F. H., and Stevens, R. C. (2014) Insights into the structure of class B GPCRs. Trends Pharmacol. Sci. 35, 12-22
11. Lagerström, M. C., and Schiöth, H. B. (2008) Structural diversity of G protein-coupled receptors and significance for drug discovery. Nat. Rev. Drug. Discov. 7, 339-357
12. De Amici, M., Dallanoce, C., Holzgrabe, U., Tränkle, C., and Mohr, K. (2010) Allosteric ligands for G protein-coupled receptors: a novel strategy with attractive therapeutic opportunities. Med. Res. Rev. 30, 463-549
13. Drucker, D. J., and Nauck, M. A. (2006) The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 368, 1696-1705
14. Deacon, C. F., Mannucci, E., and Ahrén, B. (2012) Glycaemic efficacy of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors as add-on therapy to metformin in subjects with type 2 diabetes - a review and meta analysis. Diabetes Obes. Metab. 14, 762-767
15. Morris, L. C., Nance, K. D., Gentry, P. R., Days, E. L., Weaver, C. D., Niswender, C. M., Thompson, A. D., Jones, C. K., Locuson, C. W., Morrison, R. D., Daniels, J. S., Niswender, K. D., and Lindsley, C. W. (2014) Discovery of (S)-2-cyclopentyl-N-((1-isopropylpyrrolidin2-yl)-9-methyl-1-oxo-2,9-dihydro-1H-pyrrido[3,4-b]indole-4-carboxamide (VU0453379): a novel, CNS penetrant glucagon-like peptide 1 receptor (GLP-1R) positive allosteric modulator (PAM). J. Med. Chem. 57, 10192-10197
16. Willard, F. S., Bueno, A. B., and Sloop, K. W. (2012) Small molecule drug discovery at the glucagon-like peptide-1 receptor. Exp. Diabetes Res. 2012, 709893
17. Knudsen, L. B., Kiel, D., Teng, M., Behrens, C., Bhumralkar, D., Kodra, J. T., Holst, J. J., Jeppesen, C. B., Johnson, M. D., de Jong, J. C., Jorgensen, A. S., Kercher, T., Kostrowicki, J., Madsen, P., Olesen, P. H., et al. (2007) Small-molecule agonists for the glucagon-like peptide 1 receptor. Proc. Natl. Acad. Sci. U.S.A. 104, 937-942
18. Teng, M., Truesdale, L. K., and Bhumralkar, D. (July 20, 2000) U. S. Patent WO2000/42026
19. Sloop, K. W., Willard, F. S., Brenner, M. B., Ficorilli, J., Valasek, K., Showalter, A. D., Farb, T. B., Cao, J. X., Cox, A. L., Michael, M. D., Gutierrez Sanfeliciano, S. M., Tebbe, M. J., and Coghlan, M. J. (2010) Novel small molecule glucagon-like peptide-1 receptor agonist stimulates insulin secretion in rodents and from human islets. Diabetes 59, 3099-3107
20. Willard, F. S., Wootten, D., Showalter, A. D., Savage, E. E., Ficorilli, J., Farb, T. B., Bokvist, K., Alsina-Fernandez, J., Furness, S. G., Christopoulos, A., Sexton, P. M., and Sloop, K. W. (2012) Small molecule allosteric modulation of the glucagon-like peptide-1 receptor enhances the insulinotropic effect of oxyntomodulin. Mol. Pharmacol. 82, 1066-1073
21. Koole, C., Wootten, D., Simms, J., Valant, C., Sridhar, R., Woodman, O. L., Miller, L. J., Summers, R. J., Christopoulos, A., and Sexton, P. M. (2010) Allosteric ligands of the glucagon-like peptide 1 receptor (GLP-1R) differentially modulate endogenous and exogenous peptide responses in a pathway-selective manner: implications for drug screening. Mol. Pharmacol. 78, 456-465
22. Wootten, D., Savage, E. E., Valant, C., May, L. T., Sloop, K. W., Ficorilli, J., Showalter, A. D., Willard, F. S., Christopoulos, A., and Sexton, P. M. (2012) Allosteric modulation of endogenous metabolites as an avenue for drug discovery. Mol. Pharmacol. 82, 281-290
23. Li, N., Lu, J., and Willars, G. B. (2012) Allosteric modulation of the activity of the glucagon-like peptide-1 (GLP-1) metabolite GLP-1 9-36 amide at the GLP-1 receptor. PLoS ONE 7, e47936
24. Wootten, D., Savage, E. E., Willard, F. S., Bueno, A. B., Sloop, K. W., Christopoulos, A., and Sexton, P. M. (2013) Differential activation and modulation of the glucagon-like peptide-1 receptor by small molecule ligands. Mol. Pharmacol. 83, 822-834
25. Eng, H., Sharma, R., McDonald, T. S., Edmonds, D. J., Fortin, J. P., Li, X., Stevens, B. D., Griffith, D. A., Limberakis, C., Nolte, W. M., Price, D. A., Jackson, M., and Kalgutkar, A. S. (2013) Demonstration of the innate electrophilicity of 4-(3-(benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl) pyrimidine (BETP), a small-molecule positive allosteric modulator of the glucagon-like peptide-1 receptor. Drug Metab. Dispos. 41, 1470-1479
26. Nolte, W. M., Fortin, J. P., Stevens, B. D., Aspnes, G. E., Griffith, D. A., Hoth, L. R., Ruggeri, R. B., Mathiowetz, A. M., Limberakis, C., Hepworth, D., and Carpino, P. A. (2014) A potentiator of orthosteric ligand activity at GLP-1R acts via covalent modification. Nat. Chem. Biol. 10, 629-631
27. Moon, H. S., Yang, J. S., Kim, M. K., Kim, J. K., Lee, J. Y., Kang, S. M., Kim, H. D., Shin, C. Y., Cheong, Y. H., Yang, E. K., Choi, S. H., Park, Y. S., Kim, E. J., Chae, Y. N., Cho, E. J., Son, M. H., and Kim, S. H. (October 6, 2011) U. S. Patent WO2011/122815
28. Knudsen, S. M., Pettersson, I., Lau, J., Behrens, C., Petersen, A. K., and Garibay, P. W. (January 12, 2006) U. S. Patent WO2006/003096
29. Kopin, A. S., and Beingorn, M. (December 2, 2004) U. S. Patent WO2004/203310
30. Gong, Y., Cheon, H. G., Lee, T., and Kang, N. S. (2010) A novel 3-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-yl)phenyl acetate skeleton and pharmacophore model as glucagon-like peptide 1 receptor agonists. Bull. Korean Chem. Soc. 31, 3760-3764
31. Goerdeler, J., and Heller, K. H. (1964) Über 1.2. 4-Thiodiazole, XVI. Präparative und kinetische untersuchungen der nucleophilen substitution von Halogenthiodiazolen. Chemische Berichte 97, 225-237
32. Noguchi, T., Hashimoto, Y., Mori, T., Kano, S., and Miyazaki, K. (1968) Studies on selective toxicity. 8. Biological activities of 1,2,4-thiadiazole derivatives. Yakugaku Zasshi 88, 1437-1449
33. + channel-dependent and-independent glucose-stimulated insulin secretion. Diabetes 49, 424-430
34. Ronnebaum, S. M., Jensen, M. V., Hohmeier, H. E., Burgess, S. C., Zhou, Y. P., Qian, S., MacNeil, D., Howard, A., Thornberry, N., Ilkayeva, O., Lu, D., Sherry, A. D., and Newgard, C. B. (2008) Silencing of cytosolic or mitochondrial isoforms of malic enzyme has no effect on glucose-stimulated insulin secretion from rodent islets. J. Biol. Chem. 283, 28909-28917
35. Jun, L. S., Showalter, A. D., Ali, N., Dai, F., Ma, W., Coskun, T., Ficorilli, J. V., Wheeler, M. B., Michael, M. D., and Sloop, K. W. (2014) A novel humanized GLP-1 receptor model enables both affinity purification and Cre-LoxP deletion of the receptor. PLoS ONE 9, e93746
36. Campbell, R. M., Dymshitz, J., Eastwood, B. J., Emkey, R., Greenen, D. P., Heerding, J. M., Johnson, D., Large, T. H., Littlejohn, T., Montrose, C., Nutter, S. E., Sawyer, B. D., Sigmund, S. K., Smith, M., Weidner, J. R., and Zink, R. W. (2004) in Assay Guidance Manual (Sittampalam, G. S., Coussens, N. P., Nelson, H., Arkin, M., Auld, D., Austin, C., Bejcek, B., Glicksman, M., Inglese, J., Iversen, P. W., Li, Z., McGee, J., McManus, O., Minor, L., Napper, A., Peltier, J. M., Riss, T., Trask, O. J., Jr., and Weidner, J., eds) www.ncbi.nlm.nih.gov/pubmed/22553865, Bethesda
37. Epps, D. E., and Taylor, B. M. (2001) A competitive fluorescence assay to measure the reactivity of compounds. Anal. Biochem. 295, 101-106
38. Takahashi, K., Ueno, T., Tanida, I., Minematsu-Ikeguchi, N., Murata, M., and Kominami, E. (2009) Characterization of CAA0225, a novel inhibitor specific for cathepsin L, as a probe for autophagic proteolysis. Biol. Pharm. Bull. 32, 475-479
39. Flanagan, M. E., Abramite, J. A., Anderson, D. P., Aulabaugh, A., Dahal, U. P., Gilbert, A. M., Li, C., Montgomery, J., Oppenheimer, S. R., Ryder, T., Schuff, B. P., Uccello, D. P., Walker, G. S., Wu, Y., Brown, M. F., et al. (2014) Chemical and computational methods for the characterization of covalent reactive groups for the prospective design of irreversible inhibitors. J. Med. Chem. 57, 10072-10079
40. Moon, H. S., Kim, M. K., and Son, M. H. (2011) The development of non-peptide glucagon-like peptide-1 receptor agonist for the treatment of type 2 diabetes. Arch. Pharm. Res. 34, 1041-1043
41. May, L. T., Leach, K., Sexton, P. M., and Christopoulos, A. (2007) Allosteric modulation of G protein-coupled receptors. Annu. Rev. Pharmacol. Toxicol. 47, 1-51
42. Liao, J., Hong, Y., Wang, Y., Von Geldern, T. W., and Zhang, K. E. (June 10, 2014) U. S. Patent 8,748,412
43. Singh, J., Dobrusin, E. M., Fry, D. W., Haske, T., Whitty, A., and Mc-Namara, D. J. (1997) Structure-based design of a potent, selective, and irreversible inhibitor of the catalytic domain of the erbB receptor subfamily of protein tyrosine kinases. J Med. Chem. 40, 1130-1135
44. Kwiatkowski, N., Zhang, T., Rahl, P. B., Abraham, B. J., Reddy, J., Ficarro, S. B., Dastur, A., Amzallag, A., Ramaswamy, S., Tesar, B., Jenkins, C. E., Hannett, N. M., McMillin, D., Sanda, T., Sim, T., et al. (2014) Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature 511, 616-620
45. Liu, Q., Sabnis, Y., Zhao, Z., Zhang, T., Buhrlage, S. J., Jones, L. H., and Gray, N. S. (2013) Developing irreversible inhibitors of the protein kinase cysteinome. Chem. Biol. 20, 146-159
46. Bruns, R. F., and Watson, I. A. (2012) Rules for identifying potentially reactive or promiscuous compounds. J. Med. Chem. 55, 9763-9772
47. Baell, J. B., and Holloway, G. A. (2010) New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. J. Med. Chem. 53, 2719-2740
48. Irwin, J. J., Duan, D., Torosyan, H., Doak, A. K., Ziebart, K. T., Sterling, T., Tumanian, G., and Shoichet, B. K. (2015) An aggregation advisor for ligand discovery. J. Med. Chem. 58, 7076-7087
49. Underwood, C. R., Garibay, P., Knudsen, L. B., Hastrup, S., Peters, G. H., Rudolph, R., and Reedtz-Runge, S. (2010) Crystal structure of glucagonlike peptide-1 in complex with the extracellular domain of the glucagonlike peptide-1 receptor. J. Biol. Chem. 285, 723-730
50. Chen, Q., Pinon, D. I., Miller, L. J., and Dong, M. (2009) Molecular basis of glucagon-like peptide 1 docking to its intact receptor studied with carboxyl-terminal photolabile probes. J. Biol. Chem. 284, 34135-34144
51. Chen, Q., Pinon, D. I., Miller, L. J., and Dong, M. (2010) Spatial approximations between residues 6 and 12 in the amino-terminal region of glucagon-like peptide 1 and its receptor: a region critical for biological activity. J. Biol. Chem. 285, 24508-24518
52. Moon, M. J., Lee, Y. N., Park, S., Reyes-Alcaraz, A., Hwang, J. I., Millar, R. P., Choe, H., and Seong, J. Y. (2015) Ligand binding pocket formed by evolutionarily conserved residues in the glucagon-like peptide-1 (GLP-1) receptor core domain. J. Biol. Chem. 290, 5696-5706
53. Moon, M. J., Kim, H. Y., Park, S., Kim, D. K., Cho, E. B., Park, C. R., You, D. J., Hwang, J. I., Kim, K., Choe, H., and Seong, J. Y. (2012) Evolutionarily conserved residues at glucagon-like peptide-1 (GLP-1) receptor core confer ligand-induced receptor activation. J. Biol. Chem. 287, 3873-3884
54. Kirkpatrick, A., Heo, J., Abrol, R., and Goddard, W. A., 3rd (2012) Predicted structure of agonist-bound glucagon-like peptide 1 receptor, a class B G protein-coupled receptor. Proc. Natl. Acad. Sci. U.S.A. 109, 19988-19993
55. Wessel, J., Chu, A. Y., Willems, S. M., Wang, S., Yaghootkar, H., Brody, J. A., Dauriz, M., Hivert, M. F., Raghavan, S., Lipovich, L., Hidalgo, B., Fox, K., Huffman, J. E., An, P., Lu, Y., et al. (2015) Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. Nat. Commun. 6, 5897
56. Bauer, R. A. (2015) Covalent inhibitors in drug discovery: from accidental discoveries to avoided liabilities and designed therapies. Drug Discov. Today 20, 1061-1073
57. Dahlin, J. L., Nissink, J. W., Strasser, J. M., Francis, S., Higgins, L., Zhou, H., Zhang, Z., and Walters, M. A. (2015) PAINS in the assay: chemical mechanisms of assay interference and promiscuous enzymatic inhibition observed during a sulfhydryl-scavenging HTS. J. Med. Chem. 58, 2091-2113
58. Copeland, R. A. (2005) Evaluation of enzyme inhibitors in drug discovery. A guide for medicinal chemists and pharmacologists. Methods Biochem. Anal. 46, 1-265
59. Plapp, B. V. (1982) Application of affinity labeling for studying structure and function of enzymes. Methods Enzymol. 87, 469-499
60. Erlanson, D. A. (2015) Learning from PAINful lessons. J. Med. Chem. 58, 2088-2090
61. Wu, R.-Y., Chen, H.-L., Wu, Y.-Y., Huang, J.-J., Lee, S.-S., and King, K.-L. (October 6, 2015) U. S. Patent 9,150,482
62. King, K., and Chein, R.-J. (November 24, 2015) U. S. Patent 9,193,665
63. Nakane, A., Gotoh, Y., Ichihara, J., and Nagata, H. (2015) New screening strategy and analysis for identification of allosteric modulators for gluca-gon-like peptide-1 receptor using GLP-1(9-36) amide. Anal. Biochem. 491, 23-30
64. Lebakken, C. S., Riddle, S. M., Singh, U., Frazee, W. J., Eliason, H. C., Gao, Y., Reichling, L. J., Marks, B. D., and Vogel, K. W. (2009) Development and applications of a broad-coverage, TR-FRET-based kinase binding assay platform. J. Biomol. Screen. 14, 924-935
65. Gelbert, L. M., Cai, S., Lin, X., Sanchez-Martinez, C., Del Prado, M., Lallena, M. J., Torres, R., Ajamie, R. T., Wishart, G. N., Flack, R. S., Neubauer, B. L., Young, J., Chan, E. M., Iversen, P., Cronier, D., et al. (2014) Preclinical characterization of the CDK4/6 inhibitor LY2835219: in vivo cell cycledependent/ independent anti-tumor activities alone/in combination with gemcitabine. Invest. New Drugs 32, 825-837