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Atiprimod

Description of atiprimod: atiprimod is orally bioavailable small molecule belonging to the azaspirane class of cationic amphiphilic agents with anti-inflammatory, antineoplastic, and antiangiogenic properties. Atiprimod inhibits the phosphorylation of signal transducer and activator of transcription 3 (STAT3), blocking the signalling pathways of interleukin-6 and vascular endothelial growth factor (VEGF) and downregulating the anti-apoptotic proteins Bcl-2, Bcl-XL, and Mcl-1, thereby inhibiting cell proliferation, inducing cell cycle arrest, and inducing apoptosis. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:   Callisto Pharmaceuticals

Atiprimod (INN, code named SK&F106615; also known as azaspirane, although this more properly refers to the class of chemicals to which atiprimod belongs) is a substance being studied in the treatment of certain multiple myelomas and other advanced cancers. Atiprimod may block the growth of tumors and the growth of blood vessels from surrounding tissue to the tumor. Atiprimod is a type of signal transduction inhibitor. It was first developed by SmithKline Beecham (now part of GlaxoSmithKline) as a potential treatment for rheumatoid arthritis.

January 7, 2008 Callisto Pharmaceuticals, Inc. announced that it has restructured its license agreement with Genzyme Corporation for Atiprimod. In August 2002, Callisto’s wholly owned subsidiary, Synergy, acquired from AnorMED Inc. worldwide exclusive rights to develop, manufacture and commercialize Atiprimod. AnorMED was acquired by Genzyme in November 2006. The restructured agreement eliminates all milestone payments and reduces royalties owed to Genzyme to single digits. In return for the reduced future payments to Genzyme, Callisto is paying an upfront fee in 2008

Synergy Pharmaceuticals, Inc. (a wholly-owned subsidiary of Callisto) entered into a license agreement with AnorMED Inc. to license Atiprimod from AnorMED. Atiprimod is a macrophage-targeting oral cytokine inhibitor which is being developed by AnorMED as a potential treatment for rheumatoid arthritis and other autoimmune diseases. Phase I trials have been successfully completed and Phase II multicenter trials have been approved by the FDA. The compound was discovered in a joint research and development program with SmithKline and French (now SmithKline Beecham, SB) but following acceptance of the Phase II protocol by the FDA, SB decided not to proceed with further development of atiprimod as a result of an internal restructuring program. All rights to atiprimod and other azaspiranes developed in this program have reverted to AnorMED. The compound was originally disclosed in European patent, EP-00310321, entitled 'Preparation of N-aminoalkyl-2-azaspiro[4.5]decanes and analogs as immunosuppressants', while a cost-effective, efficacious pilot plant synthesis has also been described. (from http://en.wikipedia.org/wiki/Atiprimod).

  1: Quintás-Cardama A, Manshouri T, Estrov Z, Harris D, Zhang Y, Gaikwad A, Kantarjian HM, Verstovsek S. Preclinical characterization of atiprimod, a novel JAK2 AND JAK3 inhibitor. Invest New Drugs. 2010 Apr 7. [Epub ahead of print] PubMed PMID: 20372971.

2: Neri P, Tassone P, Shammas M, Yasui H, Schipani E, Batchu RB, Blotta S, Prabhala R, Catley L, Hamasaki M, Hideshima T, Chauhan D, Jacob GS, Picker D, Venuta S, Anderson KC, Munshi NC. Biological pathways and in vivo antitumor activity induced by Atiprimod in myeloma. Leukemia. 2007 Dec;21(12):2519-26. Epub 2007 Sep 20. PubMed PMID: 17882285.

3: Wang M, Zhang L, Han X, Yang J, Qian J, Hong S, Samaniego F, Romaguera J, Yi Q. Atiprimod inhibits the growth of mantle cell lymphoma in vitro and in vivo and induces apoptosis via activating the mitochondrial pathways. Blood. 2007 Jun 15;109(12):5455-62. Epub 2007 Feb 22. PubMed PMID: 17317853.

4: Choudhari SR, Khan MA, Harris G, Picker D, Jacob GS, Block T, Shailubhai K. Deactivation of Akt and STAT3 signaling promotes apoptosis, inhibits proliferation, and enhances the sensitivity of hepatocellular carcinoma cells to an anticancer agent, Atiprimod. Mol Cancer Ther. 2007 Jan;6(1):112-21. PubMed PMID: 17237271.

5: Kaden S, Reissig HU. Efficient approach to the Azaspirane core of FR 901483. Org Lett. 2006 Oct 12;8(21):4763-6. PubMed PMID: 17020297.

6: Shailubhai K. Atiprimod: a multi-functional drug candidate for myeloid and other malignancies. Leuk Res. 2007 Jan;31(1):9-10. Epub 2006 Jul 24. PubMed PMID: 16860863.

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8: Amit-Vazina M, Shishodia S, Harris D, Van Q, Wang M, Weber D, Alexanian R, Talpaz M, Aggarwal BB, Estrov Z. Atiprimod blocks STAT3 phosphorylation and induces apoptosis in multiple myeloma cells. Br J Cancer. 2005 Jul 11;93(1):70-80. PubMed PMID: 15970928; PubMed Central PMCID: PMC2361492.

9: Faderl S, Ferrajoli A, Harris D, Van Q, Kantarjian HM, Estrov Z. Atiprimod blocks phosphorylation of JAK-STAT and inhibits proliferation of acute myeloid leukemia (AML) cells. Leuk Res. 2007 Jan;31(1):91-5. Epub 2006 Jul 7. PubMed PMID: 16828865.

10: Obniska J, Kamiński K. Lipophilicity characterization of new N-phenylamino-azaspiranes as potential anticonvulsant agents. Biomed Chromatogr. 2006 Nov;20(11):1185-91. PubMed PMID: 16799923.

11: Shailubhai K, Dheer S, Picker D, Kaur G, Sausville EA, Jacob GS. Atiprimod is an inhibitor of cancer cell proliferation and angiogenesis. J Exp Ther Oncol. 2004 Dec;4(4):267-79. PubMed PMID: 15844657.

12: Hamasaki M, Hideshima T, Tassone P, Neri P, Ishitsuka K, Yasui H, Shiraishi N, Raje N, Kumar S, Picker DH, Jacob GS, Richardson PG, Munshi NC, Anderson KC. Azaspirane (N-N-diethyl-8,8-dipropyl-2-azaspiro [4.5] decane-2-propanamine) inhibits human multiple myeloma cell growth in the bone marrow milieu in vitro and in vivo. Blood. 2005 Jun 1;105(11):4470-6. Epub 2005 Feb 10. PubMed PMID: 15705788; PubMed Central PMCID: PMC1895034.

13: Brummond KM, Hong SP. A formal total synthesis of (-)-FR901483, using a tandem cationic aza-Cope rearrangement/Mannich cyclization approach. J Org Chem. 2005 Feb 4;70(3):907-16. PubMed PMID: 15675848.

14: Ousmer M, Braun NA, Bavoux C, Perrin M, Ciufolini MA. Total synthesis of tricyclic azaspirane derivatives of tyrosine: FR901483 and TAN1251C. J Am Chem Soc. 2001 Aug 8;123(31):7534-8. PubMed PMID: 11480973.

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16: Griswold DE, Martin LD, Badger AM, Breton J, Chabot-Fletcher M. Evaluation of the cutaneous anti-inflammatory activity of azaspiranes. Inflamm Res. 1998 Feb;47(2):56-61. PubMed PMID: 9535542.

17: Bradbeer JN, Kapadia RD, Sarkar SK, Zhao H, Stroup GB, Swift BA, Rieman DJ, Badger AM. Disease-modifying activity of SK&F 106615 in rat adjuvant-induced arthritis. Multiparameter analysis of disease magnetic resonance imaging and bone mineral density measurements. Arthritis Rheum. 1996 Mar;39(3):504-14. PubMed PMID: 8607900.

18: High WB, Bugelski PJ, Nichols ME, Swift BA, Solleveld HA, Badger AM. Effects of a novel azaspirane (SK&F 105685) on arthritic lesions in the adjuvant Lewis rat: attenuation of the inflammatory process and preservation of skeletal integrity. J Rheumatol. 1994 Mar;21(3):476-83. PubMed PMID: 8006892.

19: Schmidbauer G, Hancock WW, Badger AM, Kupiec-Weglinski JW. Induction of nonspecific x-irradiation-resistant suppressor cell activity in vivo and prolongation of vascularized allograft survival by SK&F 105685, a novel immunomodulatory azaspirane. Transplantation. 1993 Jun;55(6):1236-43. PubMed PMID: 8516808.

20: Fan PY, Albrightson CR, Howell DN, Best C, Badger AM, Coffman TM. The azaspirane SKF 105685 ameliorates renal allograft rejection in rats. J Am Soc Nephrol. 1993 Apr;3(10):1680-5. PubMed PMID: 8318684.

21: Kaplan JM, Badger AM, Ruggieri EV, Swift BA, Bugelski PJ. Effects of SK&F 105685, a novel anti-arthritic agent, on immune function in the dog. Int J Immunopharmacol. 1993 Feb;15(2):113-23. PubMed PMID: 8468115.

22: Badger AM, Swift BA. Therapeutic activity of SK&F 105685, a novel azaspirane with suppressor-cell inducing activity. Clin Exp Rheumatol. 1993 Mar-Apr;11 Suppl 8:S107-9. PubMed PMID: 8324933.

23: Rabinovitch A, Suarez WL, Qin HY, Power RF, Badger AM. Prevention of diabetes and induction of non-specific suppressor cell activity in the BB rat by an immunomodulatory azaspirane, SK&F 106610. J Autoimmun. 1993 Feb;6(1):39-49. PubMed PMID: 8457285.

24: Thiem PA, Kaplan JM, Bugelski PJ, Ruggieri EV, Badger AM. Induction of suppressor cell activity in vivo and suppression of lymphoproliferative responses in vitro by SK&F 105.685 in the dog. Immunopharmacology. 1992 Mar-Apr;23(2):67-74. PubMed PMID: 1534791.

25: Kaplan JM, Badger AM, Ruggieri EV, Olivera DL, Newman-Tarr T, Bugelski PJ. Inhibition of lymphoproliferative responses by SK&F 105685, a novel anti-arthritic agent. J Clin Lab Immunol. 1991 Dec;36(4):49-58. PubMed PMID: 1668843.

26: King AG, Badger AM. Administration of an immunomodulatory azaspirane, SK&F 105685, or human recombinant interleukin 1 stimulates myelopoiesis and enhances survival from lethal irradiation in C57Bl/6 mice. Exp Hematol. 1991 Aug;19(7):624-8. PubMed PMID: 1893948.

27: Badger AM, King AG, Talmadge JE, Schwartz DA, Picker DH, Mirabelli CK, Hanna N. Induction of non-specific suppressor cells in normal Lewis rats by a novel azaspirane SK&F 105685. J Autoimmun. 1990 Aug;3(4):485-500. PubMed PMID: 2145847.

28: Mirabelli CK, Badger AM, Sung CP, Hillegass L, Sung CM, Johnson RK, Picker D, Schwartz D, Dorman J, Martellucci S. Pharmacological activities of spirogermanium and other structurally related azaspiranes: effects on tumor cell and macrophage functions. Anticancer Drug Des. 1989 Mar;3(4):231-42. PubMed PMID: 2930625.

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