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United States Patent B-Alanine Dose Dependence Of US007056685B1 (12) United States Patent (10) Patent No.: US 7,056,685 B1 Chen et al. (45) Date of Patent: Jun. 6, 2006 (54) RECEPTOR LIGANDS AND METHODS OF 6,448,230 B1 9/2002 Ruben et al. MODULATING RECEPTORS 6,555,339 B1 4/2003 Liaw et al. 6,680,373 B1 1/2004 Conley et al. (75) Inventors: Jin-Long Chen, San Mateo, CA (US); 29:92. A. 29: R al 1 Lei Ling, Foster City, CA (US); Hui CCCK ( a. Tian, Foster City, CA (US) 2004, OO19109 A1 1/2004 Owman et al. FOREIGN PATENT DOCUMENTS (73) Assignee: Amgen Inc., Thousands Oaks, CA (US) DE 10046970 A1 4/2002 (*) Notice: Subject to any disclaimer, the term of this EP 853126 A2 7, 1998 EP 859053 A1 8, 1998 patent is extended or adjusted under 35 EP 1094.076 A1 4, 2001 U.S.C. 154(b) by 0 days. EP 1178053 A2 2?2002 GB 2365O12 A 2, 2002 (21) Appl. No.: 10/703,145 GB 2369364. A 5, 2002 GB 1219638 A2 T 2002 (22) Filed: Nov. 5, 2003 JP 10304887 11, 1998 WO WO 95,24411 A1 9, 1995 Related U.S. Application Data WO WO 97/20045 A2 6, 1997 WO WO 97.24929 A1 7/1997 (60) Provisional application No. 60/424,093, filed on Nov. WO WO 98.40483 A2 9, 1998 5, 2002. WO WO 99/15858 A2 4f1999 WO WOOO 14229 A1 3, 2000 (51) Int. Cl. WO WOOO,22129 A1 4, 2000 GOIN 33/53 (2006.01) GOIN 33/00 (2006.01) (Continued) CI2P 2/06 (2006.01) OTHER PUBLICATIONS C07K I4/00 (2006.01) (52) U.S. Cl. ..................... 435/7.1; 435/7.93; 435/69.1; see Bowie et. al., Science 247: 1306-1310, 1990.* 530/350; 436/129 (Continued) (58) Field of Classification Search ................ 530/350, 530/300; 435/6, 7.1, 7.93, 7.95: 436/129; Primary Examiner Eileen B. O'Hara 35/69.1 (74) Attorney, Agent, or Firm Banner & Witcoff, Ltd. See application file for complete search history. (57) ABSTRACT (56) References Cited U.S. PATENT DOCUMENTS The invention provides natural ligands of various receptors and methods of identifying modulators of various receptors 5,436,128 A 7/1995 Harpold et al. using the ligands. Methods of using the modulators to treat 5,714,566 A 2f1998 Lubowtiz et al. 5,871,963 A 2/1999 Conley et al. diseases or disorder associated with dysfunction of the 5,910,430 A 6/1999 Bergsma et al. receptor are also provided. 6,008.322 A 12/1999 Kuestner et al. 6,063,582 A 5/2000 Conley et al. 5 Claims, 10 Drawing Sheets B-Alanine Dose Dependence of TGR2 in CHO Cells EC50 9.106e-006 -6 -5 -4 Concentration (log,M) US 7,056,685 B1 Page 2 FOREIGN PATENT DOCUMENTS Baldwin et al.; Baillieres Clin. Endocrinol. Metab. 1994; WO WOOO,221.31 A2 4/2000 8(1):185-214. WO WOOO,31258 A2 6, 2000 Barak, Larry S. et al.: “Internal Trafficking and Surface WO WOOOf 61628 A1 10, 2000 Mobility of a Functionality Intact f-Adrenergic Receptor WO WO O1/36471 A2 5, 2001 Green Fluorescent Protein Conjugate’: Molecular Pharma WO WO O1/36473 A2 5, 2001 cology: 1997: 51:177-184. WO WO Of 48188 A1 T 2001 WO WO O1? 48.189 A1 T 2001 Berridge, Michael J. & Robin F. Irvine: “Inositol WO WO O1/49847 A2 T 2001 triphosphate, a novel second messenger in cellular signal WO WO O1, 55.338 A2 8, 2001 transduction': Nature: 1984; 312:315-321. WO WO O1, 57085 A2 8, 2001 Buck, Linda & Richard Axel; “A Novel Multigene Family WO WO O1, 57.190 A2 8, 2001 May Encode Odorant Receptors: A Molecular Basis for WO WO O1? 61359 A2 8, 2001 Odor Recognition'; Cell: 1991; 65:175-187. WO WO O1? 62797 A2 8, 2001 WO WO O1.68750 A2 9, 2001 Chang, Andy C.-M. et al.: “A novel human cDNA highly WO WOO 1/70814 A2 9, 2001 homologous to the fish hormone stanniocalcin': Mol. Cell. WO WOO 1/79449 A2 10, 2001 Endocrinol. 1995; 112:241-247. WO WO O1/83555 A2 11/2001 Dhallan, Ravinder S. et al.; “Primary structure and func WO WO 01/83748 A1 11, 2001 tional expression of a cyclic nucleotide-activated channel WO WO O1/87937 A2 11/2001 from olfactory neurons'; Nature: 1990; 347:184-187. WO WO O1/8798O A2 11/2001 WO WO 01/90304 A2 11/2001 Felley-Bosco et al.; Am. J. Resp. Cell and Mol. Biol. 1994: WO WO O1/98330 A2 12/2001 11:159-164. WO WO O1 (98.351 A2 12/2001 Fong, Tung Ming: “Mechanistic Hypotheses for the Acti WO WO O2/OOT19 A2 1, 2002 vation of G-Protein-Coupled Receptors”; Cell Signal; 1996; WO WO O2/14511 A2 2, 2002 8(3):217-224. WO WO O2/16548 A2 2, 2002 Hsu, Sheau Yu et al., “The Three Subfamilies of Leucine WO WO O2/46414 A2 6, 2002 Rich Repeat-Containing G Protein-Coupled Receptors WO WO O2,53737 A1 T 2002 WO WO O2,557 O2 A2 T 2002 (LGR): Identification of LGR6 and LGR7 and the Signaling WO WO O2,57441 A1 T 2002 Mechanism for LGR7: Molecular Endocrinology; 2000; WO WO O2,57452 A2 T 2002 14(8): 1257-1271. WO WO O2,57783 A2 T 2002 Kyte, Jack & Russell F. Doolitle: “A Simple Method for WO WO O2,61087 A2 8, 2002 Displaying the Hydropathic Character of a Protein': J. Mol. WO WO O2,68591 A2 9, 2002 Biol. 1982: 157:105-132. WO WO O2,881.83 A2 11/2002 Misteli, Tom & David L. Spector; “Applications of the green WO WO O3,OOO893 A2 1, 2003 fluorescent protein in cell biology and biotechnology': WO WO 03/039443 A2 5, 2003 Nature Biotechnology: 1997: 15:961-964. WO WO O3,068959 A1 8, 2003 Murray, Ian et al.: “Acylation-stimulating protein (ASP): OTHER PUBLICATIONS structure-function determinants of cell Surface binding and triacylglycerol synthetic activity”; Biochem. J., 1999; Wells, Biochemistry 29:8509-8517, 1990.* 342:41-48. Altenhofen, W. et al.: “Control of ligand specificity in cyclic Offermanns, Stefan & Melvin I. Simon: “GOs and Glo. nucleotide-gated channels from rod photoreceptors and Couple a Wide Variety of Receptors to Phospholipase C': olfactory epitheilum: Proc. Natl. Acad. Sci. USA; Nov. The Journal of Biological Chemistry; 1995: 270(25):15175 1991; 88: 9868-9872. 1518O. An, Songzhu et al., “Identification and characterization of a melanin-concentrating hormone receptor. Proc. Natl. Acad. Wilkie, Thomas M. et al.: “Characterization of G-protein C. Sci. USA; Jun. 19, 2001: 98(13):7578-7581. subunits in the G class: Expression in murine tissues and in Baldo, Allain et al.: “ The Adipsin-Acylation Stimulating stromal and hematopoietic cell lines’; Proc. Natl. Acad. Sci. Protein System and Regulation of Intracellular Triglyceride USA; Nov. 1991; 88: 10049-10053. Synthesis”; J. Clin. Invest. 1993; 92:1543-1547. * cited by examiner U.S. Patent Jun. 6, 2006 Sheet 1 of 10 US 7,056,685 B1 FIGURE 1. B-Alanine Dose Dependence of TGR2 in CHO Cells 5000 E- 4000 1. B. ?t 3000 is: ... 2000 EC50 9.106e-006 } : 1000 O -7 -6 -5 -4 Concentration (log,M) U.S. Patent Jun. 6, 2006 Sheet 2 of 10 US 7,056,685 B1 Figure 2 GPR43-Aequorin-Short chain FAS 20OOOOO 15OOOOO EC50 I acetic 140 uM 1OOOOOO A propionic 125 uM v isobutyric 840 M 50OOOO O -6 -5 -4 -3 -2 -1 U.S. Patent Jun. 6, 2006 Sheet 3 of 10 US 7,056,685 B1 Figure 3 EC50 /N/ COOH butyric acid >1000 uM / N/N/ COOH hexanoic acid 834 uM / N/N/N/ COOH octanoic acid 17 uM / N/N/N/N/ COOH decanoic acid 78 uM /N/N/N/N/N/ COOH dodecanoic acid 43 uM /N/N/N/N/N/N/ COOH tetradecanoic acid -40 uM /N/N/N/N/N/N/N/ COOH hexadecanoic acid ~40 uM /N/N/N/N/N/N/N/N/ COO octadecanoic acid N/D /N/N/N/N/N/N/N/N/N/ COOH Arachidic acid >1000 uM U.S. Patent Jun. 6, 2006 Sheet 4 of 10 US 7,056,685 B1 Figure 4 EC50 C COOH Docosatetraaenoic acid 8.1 uM rea pro- N/N/ COOH COO Docosapentaenoic acid 6.0 uM COOH Docosahexaenoic acid 4.0 uM Eicosatetraenoic acid (arachidonic) 23.1 uM Eicosapentaenoic acid 13.8 uM U.S. Patent US 7,056,685 B1 000009?. 000000|| 000009 u J On be U.S. Patent Jun. 6, 2006 Sheet 7 of 10 US 7,056,685 B1 FLIPR (293.TGR18 stable cells) EC50 (uM) I Succinic acid 27 a maleic acid 284. y succinyl anhydride 30 • methylmalonic acid 134 o fumaric acid o T984 6.7 Figure 6B U.S. Patent Jun. 6, 2006 Sheet 8 of 10 US 7,056,685 B1 O OH 4. OH HO HO O O Succinic acid fumaric acid O OH HO OH O O O Oxalacetic acid methylmalonic acid itaConic acid N O OO O H Succinic anhydride Succinimide O HO--- succinic acid semialdehyde Figure 6C U.S. Patent Jun. 6, 2006 Sheet 9 of 10 US 7,056,685 B1 CHO cells transiently transfected with TGR164 (aequorin assay on Lumat) 1 OOOOO g-Ketoglutaric acid 246 9. v Succinic acid 59 75000 o ItaConic acid 94 9. o, Glutaric acid 363 50000 o Fumaric acid f 25000 9.
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