Overview

Selected References for Chemokine-Based Therapeutics

Overcoming hurdles in developing successful drugs targeting chemokine receptors. Schall TJ, Proudfoot AE. Nat Rev Immunol. 2011; 11(5):355-63.

Pharmacokinetic and pharmacodynamic evaluation of the novel CCR1 antagonist CCX354-C in healthy human subjects: Implications for Phase 2 dose selection. Dairaghi DJ, Zhang P, Wang Y, Seitz LC, Johnson DA, Miao S, Ertl LS, Zeng Y, Powers JP, Pennell AM, Bekker P, Schall TJ, Jaen JC. Clin Pharmacol Ther. 2011; 89(5):726-34.

CXCR7 regulates CXCL12-enhanced transendothelial migration of cancer cells. Zabel BA, Lewén S, Berahovich R, Jaen JC, Schall TJ. Molecular Cancer 2011; 10(1):73.

CXCR7 Protein expression in human adult brain and differentiated neurons. Shimizu S, Brown M, Sengupta R, Penfold ME, Meucci O. PLoS ONE 2011; 6(5): e20680.

CXCR7 influences leukocyte entry into the CNS parenchyma by controlling abluminal CXCL12 abundance during autoimmunity. Cruz-Orengo L, Holman DW, Dorsey D, Zhou L, Zhang P, Wright M, McCandless EE, Patel JR, Luker GD, Littman DR, Russell JH, Klein RS. J Exp Med. 2011; 208(2):327-39.

Characterization of CCX282-B, an orally bioavailable antagonist of the CCR9 chemokine receptor, for treatment of inflammatory bowel disease. Walters MJ, Wang Y, Lai N, Baumgart T, Zhao BN, Dairaghi DJ, Bekker P, Ertl LS, Penfold ME, Jaen JC, Keshav S, Wendt E, Pennell A, Ungashe S, Wei Z, Wright JJ, Schall TJ. J Pharmacol Exp Ther. 2010; 335(1):61-9.

CXCR7 protein is not expressed on human or mouse leukocytes. Berahovich RD, Zabel BA, Penfold ME, Lewén S, Wang Y, Miao Z, Gan L, Pereda J, Dias J, Slukvin II, McGrath KE, Jaen JC, Schall TJ. J Immunol. 2010; 185(9):5130-9.

Pathogenic role of CXCR7 in rheumatoid arthritis. Watanabe K, Penfold ME, Matsuda A, Ohyanagi N, Kaneko K, Miyabe Y, Matsumoto K, Schall TJ, Miyasaka N, Nanki T. Arthritis Rheum. 2010; 62(11):3211-20.

The chemokine receptor CXCR7 is highly expressed in human glioma cells and mediates antiapoptotic effects. Hattermann K, Held-Feindt J, Lucius R, Müerköster SS, Penfold ME, Schall TJ, Mentlein R. Cancer Res. 2010; 70(8):3299-308.

CXCR7 protein expression correlates with elevated MMP-3 secretion in breast cancer cells. Zabel BA, Miao Z, Lai NL, Wang Y, Lewen S, Berahovich RD, Jaen JC, Schall TJ. Oncology Letters 2010; 1(5):845-847.

The chemokine receptor CXCR7 is expressed on lymphatic endothelial cells during renal allograft rejection. Neusser MA, Kraus AK, Regele H, Cohen CD, Fehr T, Kerjaschki D, Wüthrich RP, Penfold ME, Schall T, Segerer S. Kidney Int. 2010; 77(9):801-8.

GSK-1605786, a selective small-molecule antagonist of the CCR9 chemokine receptor for the treatment of Crohn's disease. Eksteen B, Adams DH. IDrugs. 2010;13(7):472-81.

Chemokines and chemokine receptors in arthritis. Szekanecz Z, Vegvari A, Szabo Z, Koch A. Frontiers in Bioscience, Scholar Edition 2010; S2(1):153-167.

Anti-chemokine small molecule drugs: a promising future? Proudfoot AEI, Power CA, Schwarz MK. Expert Opin Invest Drugs 2010; 19(3):345-355.

Elucidation of CXCR7-mediated signaling events and inhibition of CXCR4-mediated tumor cell transendothelial migration by CXCR7 ligands. Zabel BA, Wang Y, Lewén S, Berahovich RD, Penfold ME, Zhang P, Powers J, Summers BC, Miao Z, Zhao B, Jalili A, Janowska-Wieczorek A, Jaen JC, Schall TJ. J Immunol. 2009; 183(5):3204-11.

Chemokines as novel therapeutic targets for inflammatory bowel disease. Nishimura M, Kuboi Y, Muramoto K, Kawano T, Imai T. Annals New York Acad. Sciences 2009; 1173(Contemporary Challenges in Autoimmunity):350-356.

Chemokines and chemokine receptors as therapeutic targets in chronic kidney disease. Vielhauer V, Anders H-J. Frontiers in Bioscience, Scholar Edition 2009; S1(1):1-12.

The role of chemokines in glomerulonephritis. Wada T, Matsushima K, Kaneko S. Frontiers in Bioscience 2008; 13:3966-3974.

The role of CXCR7/RDC1 as a chemokine receptor for CXCL12/ SDF-1 in prostate cancer. Wang J, Shiozawa Y, Wang J, Wang Y, Jung Y, Pienta KJ, Mehra R, Lober R, Taichman RS. J Biol Chem. 2008; 283(7): 4283-94.

CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor-associated vasculature. Miao Z, Luker KE, Summers BC, Berahovich R, Bhojani MS, Rehemtulla A, Kleer CG, Essner JJ, Nasevicius A, Luker GD, Howard MC, Schall TJ. Proc Natl Acad Sci U S A. 2007; 104(40):15735-40.

Proinflammatory proteases liberate a discrete high-affinity functional FPRL1 (CCR12) ligand from CCL23. Miao Z, Premack BA, Wei Z, Wang Y, Gerard C, Showell H, Howard M, Schall TJ, Berahovich R. J Immunol. 2007;178(11):7395-404.

Discovery and optimization of a series of quinazolinone-derived antagonists of CXCR3. Johnson M, Li AR, Liu J, Fu Z, Zhu L, Miao S, Wang X, Xu Q, Huang A, Marcus A, Xu F, Ebsworth K, Sablan E, Danao J, Kumer J, Dairaghi D, Lawrence C, Sullivan T, Tonn G, Schall T, Collins T, Medina J. Bioorg Med Chem Lett. 2007; 17(12): 3339-43.

A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. Burns JM, Summers BC, Wang Y, Melikian A, Berahovich R, Miao Z, Penfold ME, Sunshine MJ, Littman DR, Kuo CJ, Wei K, McMaster BE, Wright K, Howard MC, Schall TJ. J Exp Med. 2006;203(9):2201-13.

Evidence for NK cell subsets based on chemokine receptor expression. Berahovich RD, Lai NL, Wei Z, Lanier LL, Schall TJ. J Immunol. 2006;177(11):7833-40.

Optimization of 2-aminothiazole derivatives as CCR4 antagonists. Wang X, Xu F, Xu Q, Mahmud H, Houze J, Zhu L, Akerman M, Tonn G, Tang L,McMaster BE, Dairaghi DJ, Schall TJ, Collins TL, Medina JC. Bioorg Med Chem Lett. 2006;16(10):2800-3.

Kidney diseases and chemokines. Panzer U, Steinmetz OM, Stahl RAK, Wolf G. Current Drug Targets 2006; 7(1):65-80.

Proteolytic activation of alternative CCR1 ligands in inflammation. Berahovich RD, Miao Z, Wang Y, Premack B, Howard MC, Schall TJ. J Immunol. 2005;174(11):7341-51.

Recent ChemoCentryx Abstracts

Safety and Efficacy of Oral Chemokine Receptor 1 Antagonist CCX354-C in a Phase 2 Rheumatoid Arthritis Study. Tak PP, Balanescu AR, Tseluyko V, Bojin S, Galatikova D, Drescher E, Szombati I, Hrycaj P, Dairaghi D, Miao S, Marchesin V, Jaen J, Bekker P, Schall TJ; Annual Meeting of the American College of Rheumatology, Chicago (IL); November 8, 2011. Late-Breaking Abstract # L5 (selected for oral presentation).

Inhibition of the CCR2 chemokine receptor in diabetic mice results in a rapid and robust improvement of renal function including albuminuria. Sullivan T, Miao Z, Zhao N, Berahovich R, Powers JP, Ertl L, Dang T, Zhao R, Liu S, Miao S, Seitz LC, Bekker P, Schall TJ, Jaen JC; 44th Annual Meeting of the American Society of Nephrology, Philadelphia (PA); November 8-13, 2011. Abstract # TH-PO537.

Inhibition of the CCR2 chemokine receptor in diabetic mice results in a rapid and robust improvement of hyperglycemia. Jaen JC, Sullivan T, Miao Z, Zhao N, Berahovich R; Ertl L; Baumgart T, Krasinski A; Greenman K; Bekker P; Powers J; Schall T; European Association for the Study of Diabetes, Lisbon, Portugal; Sept 12-16, 2011. Abstract # 894.

Safety and efficacy of oral chemokine receptor 2 antagonist CCX140-B in a Phase 2 Type 2 Diabetes Mellitus study. Hanefeld M, Schell E, Gouni-Berthold I, Melichar M, Vesela I, Sullivan T, Miao S, Johnson D, Jaen J, Bekker P, Schall TJ. European Association for the Study of Diabetes, Lisbon, Portugal; Sept 12-16, 2011. (selected for oral presentation).

CCR2 antagonism improves renal function and hyperglycemia in preclinical models of Type 2 diabetes. Sullivan T, Miao Z, Berahovich R, Zhao N, Charvat T, Powers J, Jaen JC, Schall TJ; 71st American Diabetes Association Scientific Sessions, San Diego (CA); June 24-28, 2011. Abstract # 606-P.

Oral Chemokine Receptor 2 Antagonist CCX140-B Shows Safety and Efficacy in Type 2 Diabetes Mellitus. Hanefeld M, Schell E, Gouni-Berthold I, Melichar M, Vesela I, Sullivan T, Miao S, Johnson D, Jaen J, Bekker P, Schall TJ; 71st American Diabetes Association Scientific Sessions, San Diego (CA); June 24-28, 2011. Abstract #310-OR (selected for oral presentation).

CCR1 blockade by an orally-available CCR1 antagonist reduces tumor burden and osteolysis in vivo in a mouse model of myeloma bone disease. Oyajobi B, Dairaghi D, Gupta A, McCluskey B, Wang Y, Seitz LC, Powers JP, Miao S, Zhang P, Schall TJ, Jaen JC; American Society of Hematology National Meeting, Orlando (FL); December 5, 2010. Blood (2010) Nov 19 Suppl.

CCR2 antagonist inhibits neointimal proliferation post coronary stent deployment. Teramoto T, Ikeno F, Nakatani D, Otake H, Lyons JK, Sullivan T, Jaen J, Schall T, Tio F, Fearon W, Yeung AC, Fearon WF; American Heart Association National Meeting, Chicago (IL) November 17, 2010.

The novel C5aR antagonist CCX168 displays great efficacy in a mouse model of ANCA-induced glomerulonephritis. Xiao H, Jennette JC, Dairaghi D, Powers JP, Wang Y, Ertl L, Baumgart T, Miao S, Seitz LC, Hu P, Falk RJ, Schall TJ, Jaen JC. 43rd Annual Meeting of the American Society of Nephrology, Denver (CO); November 16-21, 2010. Abstract # F-FC179 (selected for oral presentation). J. Am. Soc. Nephrol. 21: 40A.

Phase 1 Clinical Pharmacokinetic and Pharmacodynamic Evaluation of the Novel C5aR Antagonist CCX168, a Potential Therapeutic for ANCA-Vasculitis. Dairaghi D, Johnson DA, Deshayes K, Miao S, Seitz L, Wang Y, Leleti MR, Powers JP, Bekker P, Schall TJ, Jaen JC; 43rd Annual Meeting of the American Society of Nephrology, Denver (CO); November 16-21, 2010. Abstract # SA-PO2111. J. Am. Soc. Nephrol. 21: 595A.

CCR1 antagonist CCX354-C in Phase 2 clinical development for Rheumatoid Arthritis. Dairaghi DJ, Marchesin V, Johnson DA, Miao S, Seitz LC, Wang Y, Zhang P, Powers JP, Ho B, Bekker PJ, Jaen JC, Schall TJ; Annual Meeting of the American College of Rheumatology, Atlanta (GA); November 3, 2010. Abstract #1100. Arthritis Rheum. (2010) 62(10S): S460.

The novel C5aR antagonist CCX168 displays great efficacy in a mouse model of ANCA-induced glomerulonephritis. Xiao H, Jennette JC, Dairaghi DJ, Ertl L, Baumgart T, Miao S, Powers JP, Seitz LC, Wang Y, Hu P, Falk RJ, Schall TJ, Jaen JC. Annual Meeting of the American College of Rheumatology, Atlanta (GA); November 3, 2010. Abstract # 2048. Arthritis Rheum. (2010) 62(10S): S856.

Phase 1 Clinical Pharmacokinetic and Pharmacodynamic Evaluation of the Novel C5aR Antagonist CCX168, a Potential Therapeutic for ANCA-Vasculitis. Dairaghi DJ, Jaen JC, Deshayes K, Johnson DA, Leleti MR, Miao M, Powers JP, Seitz LC, Wang Y, Schall TJ, Bekker PJ. Annual Meeting of the American College of Rheumatology, Atlanta (GA); November 3, 2010. Abstract # 2032. Arthritis Rheum. 62(10S): S850.

One-year results from PROTECT-1 study of intestine-specific chemokine receptor antagonist CCX282-B (Traficet-EN) in Crohn's disease. Hetzel DJ, Keshav S, Johnson D, Jaen JC, Schall TJ, Bekker P; United European Gastroenterology Week (UEGW 2010), Barcelona (Spain) October 23-27, 2010. Abstract # PO946.

CCR9 inhibition in the treatment of colonic inflammation. Jaen JC, Walters MJ, Berahovich R, Ertl L, Ebsworth K, Schall TJ; United European Gastroenterology Week (UEGW 2010), Barcelona (Spain) October 23-27, 2010. Abstract # OP459 (selected for oral presentation).

Inhibition of SDF-1/CXCR7 radiosensitizes ENU-induced glioblastomas in the rat. Tseng D, Lartey F, Liu S-C, Kioi M, Walters M, Schall TJ, Jaen JC, Merchant M, Recht L, Brown M; 56th Annual Meeting of the Radiation Research Society, Maui (HI) September 26-29, 2010.

CCR2 antagonist CCX140-B in Phase 2 for type 2 diabetes. T. Sullivan, S. Miao, R. Berahovich, N. Zhao, D. Johnson, P. Bekker, J. Jaen, T.J. Schall; European Association for the Study of Diabetes, Stockholm, Sweden; Sept 20-24, 2010. Abstract #833.

A novel CCR1 antagonist CCX354-C for rheumatoid arthritis. Dairaghi D, Ertl L, Johnson D, Pennell AM, Powers JP, Miao S, Seitz L, Wang Y, Zeng Y, Zhang P, Bekker P, Schall TJ, Jaen JC; 2010 Annual European Congress of Rheumatology (EULAR), Rome (Italy) June 16-19, 2010. Abstract # THU0203. Ann. Rheum. Dis. 69(3S):214.

Chemokine receptor antagonist CCX282-B (Traficet-EN) maintained remission of Crohn's Disease in PROTECT-1 study. Keshav S, Johnson D, Schall T, Bekker P; Digestive Disease Week, New Orleans (NO) May 1 - 5, 2010. Abstract #647.

CCR2 Antagonist Inhibits Neointimal Proliferation Post Coronary Stent Deployment. Teramoto T, Ikeno F, Otake H, Lyons JK, Sullivan T, Jaen J, Schall T, Tio F, Fearon W, Yeung AC; Amer. College Cardiol. National Meeting (ACC.10), Atlanta (GA) March 2010. Abstract #TCT-394. J. Am. Coll. Cardiol. 2010, 56(13Suppl.1), B91.

PROTECT-1 study of intestine-specific chemokine receptor antagonist CCX282-B (TRAFICET-EN) in Crohn's Disease. Keshav S, Vanasek T, Niv Y, Petryka R, Howaldt S, Bafutto M, Racz I, Hetzel D, Nielsen OH, Vermeire S, Reinisch W, Karlen P, Schreiber S, Johnson D, Schall TJ, Bekker P; GASTRO/United European Gastroenterology Week meeting, Nov 21-25, 2009, London, United Kingdom. Abstract #P1810.

CCR9 inhibition in the treatment of colonic inflammation. Walters MJ, Berahovich R, Ertl L, Ebsworth K, Baumgart T, Charvat TT, Powers JP, Punna S, Wang Y, Bekker P, Jaen JC, Schall TJ; 2009 Advances in Inflammatory Bowel Diseases; Crohn's & Colitis Foundation's Clinical & Research Conference, Hollywood, FL; December 3-6, 2009. Inflammatory Bowel Diseases 2009; 15 (suppl.):S2. Abstract #O-0011.

PROTECT-1 maintenance phase study results demonstrate efficacy of the intestine-specific chemokine receptor antagonist CCX282-B (Traficet-EN) in Crohn's Disease. Bekker P, Keshav S, Johnson D, Schall T; 2009 Advances in Inflammatory Bowel Diseases; Crohn's & Colitis Foundation's Clinical & Research Conference, Hollywood, FL; December 3-6, 2009. Inflammatory Bowel Diseases 2009; 15 (suppl.):S2. Abstract #P-0022.

TRAFICET-EN, an oral CCR9-specific antagonist, induces high levels of remission in the open-label phase of PROTECT-1 in Crohn's Disease. Schreiber S, Reinisch W, Vanasek T, Petryka R, Niv Y, Zadorova Z, Howaldt S, Haagen-Nielsen O, Bafutto M, Dahlerup J, Marlicz K, Prochazka V, Keshav S, Hamilton G, Bekker PJ, Schall TJ; 16th United European Gastroenterology Week meeting, Oct 18-22, 2008, Vienna, Austria. Abstract #OP-002.

PROTECT-1, a Prospective Randomized Oral Therapy Evaluation of CCX282-B (Trafficet-EN) in Crohn's Disease Trial. Bekker P, Petryka R, Vanásk T, Niv Y, Marlicz K, Haagen-Nielsen O, Dahlerup J, Dotan I, Compel V, Keshav S, Schall T; CCFA National Research and Clinical Conference, 6th Annual Advances in the Inflammatory Bowel Diseases, Dec 6-9, 2007, Aventura, Florida. Inflammatory Bowel Diseases 2007; 14 (suppl.):S11. Abstract #P-003.

PROTECT-1, a Prospective Randomized Oral Therapy Evaluation of CCX282-B (Traficet-EN) in Crohn's Disease Trial. Bekker P, Schreiber S, Keshav S, Petryka R, Vanásk T, Niv Y, Marlicz K, Haagen-Nielsen O, Machado M, Dahlerup J, Sankar S, Schall Y; 15th United European Gastroenterology Week meeting, Oct 27-31, 2007, Paris, France. Abstract #OP-G-106.

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