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PPI-2458

PPI-2458 is a synthetic derivative of fumagillin with antineoplastic and cytotoxic properties. PPI-2458 irreversibly inhibits the enzyme methionine aminopeptidase type 2 (MetAP2), thereby preventing abnormal cell growth and angiogenesis. PPI-2458 is reported to have a better toxicity profile compared to other agents of its class. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)

PPI-2458, a novel, orally active agent of the fumagillin class of irreversible methionine aminopeptidase-2 (MetAP-2) inhibitors, potently inhibited the proliferation of B16F10 melanoma cells in vitro, with a growth inhibitory concentration 50% (GI50) of 0.2 nM. B16F10 growth inhibition was correlated with the inhibition of MetAP-2 enzyme, in a dose-dependent fashion, as determined by a pharmacodynamic assay, which measures the amount of uninhibited MetAP-2 following PPI-2458 treatment.  The antiproliferative activity, coupled with additional observations from studies in vitro (absence of detectable resistance to PPI-2458 and induction of morphological features consistent with differentiated melanocytes), provides a rationale for assessing the therapeutic potential of PPI-2458 in the treatment of melanoma. see http://www.ncbi.nlm.nih.gov/pubmed/16525646.

Current developer:     Praecis Pharmaceutical Inc and GlaxoSmithKline

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2. Bierbach, Ulrich. Platinum acridine anti-cancer compounds and methods thereof. PCT Int. Appl. (2010), 54pp. CODEN: PIXXD2 WO 2010048499 A1 20100429 CAN 152:517954 AN 2010:529827

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4. Arico-Muendel, Christopher C.; Benjamin, Dennis R.; Caiazzo, Teresa M.; Centrella, Paolo A.; Contonio, Brooke D.; Cook, Charles M.; Doyle, Elisabeth G.; Hannig, Gerhard; Labenski, Matthew T.; Searle, Lily L.; Lind, Kenneth; Morgan, Barry A.; Olson, Gary; Paradise, Christopher L.; Self, Christopher; Skinner, Steven R.; Sluboski, Barbara; Svendsen, Jennifer L.; Thompson, Charles D.; Westlin, William; White, Kerry F. Carbamate Analogues of Fumagillin as Potent, Targeted Inhibitors of Methionine Aminopeptidase-2. Journal of Medicinal Chemistry (2009), 52(24), 8047-8056. CODEN: JMCMAR ISSN:0022-2623. CAN 152:75240 AN 2009:1472416

5. Arico-Muendel, Christopher; Centrella, Paolo A.; Contonio, Brooke D.; Morgan, Barry A.; O'Donovan, Gary; Paradise, Christopher L.; Skinner, Steven R.; Sluboski, Barbara; Svendsen, Jennifer L.; White, Kerry F.; Debnath, Anjan; Gut, Jiri; Wilson, Nathan; McKerrow, James H.; DeRisi, Joseph L.; Rosenthal, Philip J.; Chiang, Peter K. Antiparasitic activities of novel, orally available fumagillin analogs. Bioorganic & Medicinal Chemistry Letters (2009), 19(17), 5128-5131. CODEN: BMCLE8 ISSN:0960-894X. CAN 151:439926 AN 2009:1006035

6. Brahn, Ernest; Schoettler, Nathan; Lee, Sarah; Banquerigo, Mona L. Involution of collagen-induced arthritis with an angiogenesis inhibitor, PPI-2458. Journal of Pharmacology and Experimental Therapeutics (2009), 329(2), 615-624. CODEN: JPETAB ISSN:0022-3565. CAN 151:24363 AN 2009:527607

7. Hannig, Gerhard; Bernier, Sylvie. Methods for treating microphthalmia-associated transcription factor (MITF)-associated diseases by the use of methionine aminopeptidase-2 inhibitors. PCT Int. Appl. (2008), 66pp. CODEN: PIXXD2 WO 2008066641 A2 20080605 CAN 149:1517 AN 2008:674868

8. Bainbridge, John; Madden, Leigh; Essex, David; Binks, Michael; Malhotra, Rajneesh; Paleolog, Ewa M. Methionine aminopeptidase-2 blockade reduces chronic collagen-induced arthritis: potential role for angiogenesis inhibition. Arthritis Research & Therapy (2007), 9(6), No pp. given. CODEN: ARTRCV ISSN:1478-6362. CAN 149:811 AN 2008:322575

9. Lazarus, D. D.; Doyle, E. G.; Bernier, S. G.; Rogers, A. B.; Labenski, M. T.; Wakefield, J. D.; Karp, R. M.; Clark, E. J.; Lorusso, J.; Hoyt, J. G.; Thompson, C. D.; Hannig, G.; Westlin, W. F. An inhibitor of methionine aminopeptidase type-2, PPI-2458, ameliorates the pathophysiological disease processes of rheumatoid arthritis. Inflammation Research (2007), Volume Date 2008, 57(1), 18-27. CODEN: INREFB ISSN:1023-3830. CAN 148:529095 AN 2008:212111

10. Hanning, Gerhard; Westlin, William F. Methods for treating bone associated diseases by the use of methionine aminopeptidase-2 inhibitors. PCT Int. Appl. (2007), 65pp. CODEN: PIXXD2 WO 2007124005 A2 20071101 CAN 147:496380 AN 2007:1245896

11. Hannig, Gerhard; Westlin, William F. Methionine aminopeptidase-2 (MetAP-2)-based methods for assessing the efficacy of treatment with a glucocorticoid. PCT Int. Appl. (2007), 36pp. CODEN: PIXXD2 WO 2007123950 A1 20071101 CAN 147:480417 AN 2007:1242789

12. Olson, Gary L.; Self, Christopher; Lee, Lily; Cook, Charles M.; Birktoft, Jens; Morgan, Barry; Arico-Muendel, Christopher C. Preparation of amino acid derivatives as methionine aminopeptidase-2 inhibitors. U.S. Pat. Appl. Publ. (2007), 50pp., Cont.-in-part of U.S. Ser. No. 429,174. CODEN: USXXCO US 2007161570 A1 20070712 CAN 147:166629 AN 2007:763803

13. Hannig, Gerhard; Bernier, Sylvie G.; Hoyt, Jennifer G.; Doyle, Beth; Clark, Ed; Karp, Russell M.; Lorusso, Jeanine; Westlin, William F. Suppression of inflammation and structural damage in experimental arthritis through molecular targeted therapy with PPI-2458. Arthritis & Rheumatism (2007), 56(3), 850-860. CODEN: ARHEAW ISSN:0004-3591. CAN 146:492929 AN 2007:368700

14. Cooper, Andrew C.; Karp, Russell M.; Clark, Edward J.; Taghizadeh, Nazbeh R.; Hoyt, Jennifer G.; Labenski, Matthew T.; Murray, Michael J.; Hannig, Gerhard; Westlin, William F.; Thompson, Charles D. A novel methionine aminopeptidase-2 inhibitor, PPI-2458, inhibits non-Hodgkin's lymphoma cell proliferation in vitro and in vivo. Clinical Cancer Research (2006), 12(8), 2583-2590. CODEN: CCREF4 ISSN:1078-0432. CAN 145:347918 AN 2006:382700

15. Hannig, Gerhard; Lazarus, Douglas D.; Bernier, Sylvie G.; Karp, Russell M.; Lorusso, Jeanine; Qiu, Daniel; Labenski, Matthew T.; Wakefield, Jim D.; Thompson, Charles D.; Westlin, William F. Inhibition of melanoma tumor growth by a pharmacological inhibitor of MetAP-2, PPI-2458. International Journal of Oncology (2006), 28(4), 955-963. CODEN: IJONES ISSN:1019-6439. CAN 145:262618 AN 2006:334970

16. Bernier, Sylvie G.; Westlin, William F.; Hannig, Gerhard. Fumagillin class inhibitors of methionine aminopeptidase-2. Drugs of the Future (2005), 30(5), 497-508. CODEN: DRFUD4 ISSN:0377-8282. CAN 144:63695 AN 2005:1022871

17. Bernier, Sylvie G.; Taghizadeh, Nazbeh; Thompson, Charles D.; Westlin, William F.; Hannig, Gerhard. Methionine aminopeptidases type I and type II are essential to control cell proliferation. Journal of Cellular Biochemistry (2005), 95(6), 1191-1203. CODEN: JCEBD5 ISSN:0730-2312. CAN 143:417677 AN 2005:781623

18. Olson, Gary L.; Self, Christopher; Lee, Lily; Cook, Charles Michael; Birktoft, Jens; Morgan, Barry; Arico-Muendel, Christopher C. Preparation of amino acid derivatives as methionine aminopeptidase-2 inhibitors. U.S. Pat. Appl. Publ. (2005), 51 pp., Cont.-in-part of U.S. Ser. No. 138,935. CODEN: USXXCO US 2005059585 A1 20050317 CAN 142:317077 AN 2005:238675

19. Lainer, Dahlia T.; Brahn, Ernest. New antiangiogenic strategies for the treatment of proliferative synovitis. Expert Opinion on Investigational Drugs (2005), 14(1), 1-17. CODEN: EOIDER ISSN:1354-3784. CAN 142:232217 AN 2005:100214

20. Arico-Muendel, Christopher C.; Benjamin, Dennis; Thompson, Charles; Wang, Bryan; Wakefield, James; Gefter, Malcolm L. Methods of measuring the ability of a test compound to inactivate a biological target in the cells of a subject. PCT Int. Appl. (2004), 44 pp. CODEN: PIXXD2 WO 2004092728 A2 20041028 CAN 141:374689 AN 2004:906005

21. Bernier, Sylvie G.; Lazarus, Douglas D.; Clark, Edward; Doyle, Beth; Labenski, Matthew T.; Thompson, Charles D.; Westlin, William F.; Hannig, Gerhard. A methionine aminopeptidase-2 inhibitor, PPI-2458, for the treatment of rheumatoid arthritis. Proceedings of the National Academy of Sciences of the United States of America (2004), 101(29), 10768-10773. CODEN: PNASA6 ISSN:0027-8424. CAN 141:271212 AN 2004:611559

22. Olson, Gary L.; Self, Christopher; Lee, Lily; Cook, Charles Michael; Birktoft, Jens; Morgan, Barry; Arico-Muendel, Christopher C. Preparation of compounds comprising a methionine aminopeptidase 2 (MetAP-2) inhibitory core coupled to a peptide for modulation of angiogenesis. U.S. Pat. Appl. Publ. (2003), 48 pp., Cont.-in-part of U.S. Ser. No. 1,945. CODEN: USXXCO US 2003109671 A1 20030612 CAN 139:7179 AN 2003:455053

23. Olson, Gary L.; Self, Christopher; Lee, Lily; Cook, Charles Michael; Birktoft, Jens. Therapeutic agents and methods of use thereof for the modulation of angiogenesis. U.S. Pat. Appl. Publ. (2002), 38 pp., Cont.-in-part of U. S. Ser. No. 704,251. CODEN: USXXCO US 2002193298 A1 20021219 CAN 138:33374 AN 2002:965105

24. Olson, Gary L.; Self, Christopher; Lee, Lily; Cook, Charles Michael; Birktoft, Jens; Morgan, Barry; Arico-muendel, Christopher C. Preparation of amino acid compounds containing the fumagillin core for the modulation of angiogenesis. U.S. Pat. Appl. Publ. (2002), 47 pp., Cont.-in-part of U. S. Ser. No. 972,772. CODEN: USXXCO US 2002151493 A1 20021017 CAN 137:311201 AN 2002:794303

25. Olson, Gary L.; Self, Christopher; Lee, Lily; Cook, Charles Michael; Birktoft, Jens. Preparation of amino acid compounds containing the fumagillin core for the modulation of angiogenesis. PCT Int. Appl. (2002), 98 pp. CODEN: PIXXD2 WO 2002042295 A2 20020530 CAN 136:402029 AN 2002:408668

26. Priest R C; Spaull J; Buckton J; Grimley R L; Sims M; Binks M; Malhotra R Immunomodulatory activity of a methionine aminopeptidase-2 inhibitor on B cell differentiation. Clinical and experimental immunology (2009), 155(3), 514-22.

27. Bainbridge John; Madden Leigh; Essex David; Binks Michael; Malhotra Rajneesh; Paleolog Ewa M Methionine aminopeptidase-2 blockade reduces chronic collagen-induced arthritis: potential role for angiogenesis inhibition. Arthritis research & therapy (2007), 9(6), R127. 

28. Lazarus D D; Doyle E G; Bernier S G; Rogers A B; Labenski M T; Wakefield J D; Karp R M; Clark E J; Lorusso J; Hoyt J G; Thompson C D; Hannig G; Westlin W F An inhibitor of methionine aminopeptidase type-2, PPI-2458, ameliorates the pathophysiological disease processes of rheumatoid arthritis. Inflammation research : official journal of the European Histamine Research Society ... [et al.] (2008), 57(1), 18-27.

29. Lainer-Carr Dahlia; Brahn Ernest Angiogenesis inhibition as a therapeutic approach for inflammatory synovitis. Nature clinical practice. Rheumatology (2007), 3(8), 434-42.

30. Bayes Miriam Gateways to clinical trials. Methods and findings in experimental and clinical pharmacology (2007), 29(2), 153-73. J