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Telatinib

Telatinib (17-AGG)  is  an orally bioavailable, small-molecule inhibitor of several receptor protein tyrosine kinases with potential antiangiogenic and antineoplastic activities. Telatinib binds to and inhibits the vascular endothelial growth factor receptors (VEGFRs) type 2 and 3, platelet-derived growth factor receptor beta (PDGFRb) and c-Kit, which may result in the inhibition of angiogenesis and cellular proliferation in tumors in which these receptors are upregulated. These telatinib-inhibited receptor protein tyrosine kinases are overexpressed or mutated in many tumor cell types and may play key roles in tumor angiogenesis and tumor cell proliferation. 17-AAG is a synthetic analogue of the benzoquinone ansamycin antibiotic geldanamycin and has also been found to inhibit the molecular chaperone Hsp90. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).  

Current developer:    Bay healthcare Pharmaceuticals Inc.

Phase I study of Telatinib: Telatinib (450 mg b.i.d.) combined with bevacizumab (1 mg/kg bi-weekly) shows antitumor activity, but accumulating constitutional toxicity impedes long-term treatment of patients. Therefore, this combination will not be pursued in a phase II setting.  (source: Ann Oncol. 2011 Nov;22(11):2508-15).

Phase I study of Telatinib (combo study):  Twenty-three patients were included in this phase I trial. Most frequently (>25%) reported adverse events of any grade were vomiting, nausea, fatigue, diarrhea, alopecia, and hand-foot syndrome. A silent myocardial infarction and two cases of decreased left ventricular ejection fraction were reported; both were reversible. Cardiac monitoring of the subsequent patients did not reveal other abnormalities. The study was terminated when the recommended single agent phase II doses of telatinib (900 mg twice daily) and capecitabine/irinotecan was reached. Pharmacokinetic profiles showed no clinically relevant changes upon coadministration of the three drugs. (Circulating) endothelial (progenitor) cell levels stabilized during treatment. Five of 23 patients had partial remission and 9 of 23 patients showed stable disease. CONCLUSIONS:  Continuous administration of 900 mg telatinib twice daily can be safely combined with irinotecan (180 mg/m(2)) and capecitabine (1,000 mg/m(2) twice daily, day 1-14) and is the recommended schedule for further phase II studies. Tumor shrinkage and disease stabilization was observed. Cardiac toxicity needs further investigation in following studies. (source: Clin Cancer Res. 2010 Apr 1;16(7):2187-97.).

1: O'Malley KJ, Langmann G, Ai J, Ramos-Garcia R, Vessella RL, Wang Z. Hsp90 inhibitor 17-AAG inhibits progression of LuCaP35 xenograft prostate tumors to castration resistance. Prostate. 2011 Dec 7. doi: 10.1002/pros.22458. [Epub ahead of print] PubMed PMID: 22161776.

2: Liu H, Zhang T, Chen R, McConkey DJ, Ward JF, Curley SA. Multiple Kinase Pathways Involved in the Different De Novo Sensitivity of Pancreatic Cancer Cell Lines to 17-AAG. J Surg Res. 2011 Oct 5. [Epub ahead of print] PubMed PMID: 22099584.

3: Modi S, Stopeck A, Linden H, Solit D, Chandarlapaty S, Rosen N, D'Andrea G, Dickler M, Moynahan ME, Sugarman S, Ma W, Patil S, Norton L, Hannah AL, Hudis C. HSP90 inhibition is effective in breast cancer: a phase II trial of tanespimycin (17-AAG) plus trastuzumab in patients with HER2-positive metastatic breast cancer progressing on trastuzumab. Clin Cancer Res. 2011 Aug 1;17(15):5132-9. Epub 2011 May 10. PubMed PMID: 21558407.

4: Won YW, Yoon SM, Sonn CH, Lee KM, Kim YH. Nano self-assembly of recombinant human gelatin conjugated with α-tocopheryl succinate for Hsp90 inhibitor, 17-AAG, delivery. ACS Nano. 2011 May 24;5(5):3839-48. Epub 2011 May 3. PubMed PMID: 21517103.

5: Watanabe T, Nagase K, Chosa M, Tobinai K. Schwann cell autophagy induced by SAHA, 17-AAG, or clonazepam can reduce bortezomib-induced peripheral neuropathy. Br J Cancer. 2010 Nov 9;103(10):1580-7. Epub 2010 Oct 19. PubMed PMID: 20959823; PubMed Central PMCID: PMC2990589.

6: Rusmini P, Simonini F, Crippa V, Bolzoni E, Onesto E, Cagnin M, Sau D, Ferri N, Poletti A. 17-AAG increases autophagic removal of mutant androgen receptor in spinal and bulbar muscular atrophy. Neurobiol Dis. 2011 Jan;41(1):83-95. Epub 2010 Sep 9. PubMed PMID: 20816782.

7: Best OG, Singh N, Forsyth C, Mulligan SP. The novel Hsp-90 inhibitor SNX7081 is significantly more potent than 17-AAG against primary CLL cells and a range of haematological cell lines, irrespective of lesions in the TP53 pathway. Br J Haematol. 2010 Oct;151(2):185-8. PubMed PMID: 20738310.

8: Pacey S, Gore M, Chao D, Banerji U, Larkin J, Sarker S, Owen K, Asad Y, Raynaud F, Walton M, Judson I, Workman P, Eisen T. A Phase II trial of 17-allylamino, 17-demethoxygeldanamycin (17-AAG, tanespimycin) in patients with metastatic melanoma. Invest New Drugs. 2012 Feb;30(1):341-9. Epub 2010 Aug 5. PubMed PMID: 20683637.

9: Zhang T, Li Y, Zhu Z, Gu M, Newman B, Sun D. MEK Inhibition Potentiates the Activity of Hsp90 Inhibitor 17-AAG against Pancreatic Cancer Cells. Mol Pharm. 2010 Jul 29. [Epub ahead of print] PubMed PMID: 20669973; PubMed Central PMCID: PMC2992603.

10: Chandran T, Katragadda U, Teng Q, Tan C. Design and evaluation of micellar nanocarriers for 17-allyamino-17-demethoxygeldanamycin (17-AAG). Int J Pharm. 2010 Jun 15;392(1-2):170-7. Epub 2010 Apr 2. PubMed PMID: 20363305.

11: Ujino S, Yamaguchi S, Shimotohno K, Takaku H. Combination therapy for hepatitis C virus with heat-shock protein 90 inhibitor 17-AAG and proteasome inhibitor MG132. Antivir Chem Chemother. 2010 Mar 9;20(4):161-7. PubMed PMID: 20231781.

12: Riedel M, Goldbaum O, Schwarz L, Schmitt S, Richter-Landsberg C. 17-AAG induces cytoplasmic alpha-synuclein aggregate clearance by induction of autophagy. PLoS One. 2010 Jan 18;5(1):e8753. PubMed PMID: 20090920; PubMed Central PMCID: PMC2807466.

13: Usmani SZ, Bona R, Li Z. 17 AAG for HSP90 inhibition in cancer--from bench to bedside. Curr Mol Med. 2009 Jun;9(5):654-64. Review. PubMed PMID: 19601813.

14: Wang YQ, Zhang XM, Wang XD, Wang BJ, Wang W. 17-AAG, a Hsp90 inhibitor, attenuates the hypoxia-induced expression of SDF-1alpha and ILK in mouse RPE cells. Mol Biol Rep. 2010 Mar;37(3):1203-9. Epub 2009 Mar 6. PubMed PMID: 19266313.

15: Gaspar N, Sharp SY, Pacey S, Jones C, Walton M, Vassal G, Eccles S, Pearson A, Workman P. Acquired resistance to 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin) in glioblastoma cells. Cancer Res. 2009 Mar 1;69(5):1966-75. Epub 2009 Feb 24. Erratum in: Cancer Res. 2009 Apr 15;69(8):3721. PubMed PMID: 19244114; PubMed Central PMCID: PMC2652695.

16: Wenyong T, Lu L, Daozhen C, Weidong Y, Ying H. An experimental study on the antitumor effect of 131I-17-AAG in vitro and in vivo. Ann Nucl Med. 2009 Feb;23(2):113-22. Epub 2009 Feb 19. PubMed PMID: 19225933.

17: Siegelin MD, Habel A, Gaiser T. 17-AAG sensitized malignant glioma cells to death-receptor mediated apoptosis. Neurobiol Dis. 2009 Feb;33(2):243-9. Epub 2008 Nov 10. PubMed PMID: 19027068.

18: Raja SM, Clubb RJ, Bhattacharyya M, Dimri M, Cheng H, Pan W, Ortega-Cava C, Lakku-Reddi A, Naramura M, Band V, Band H. A combination of Trastuzumab and 17-AAG induces enhanced ubiquitinylation and lysosomal pathway-dependent ErbB2 degradation and cytotoxicity in ErbB2-overexpressing breast cancer cells. Cancer Biol Ther. 2008 Oct;7(10):1630-40. Epub 2008 Oct 9. PubMed PMID: 18769124; PubMed Central PMCID: PMC2727620.

19: Xiong MP, Yáñez JA, Kwon GS, Davies NM, Forrest ML. A cremophor-free formulation for tanespimycin (17-AAG) using PEO-b-PDLLA micelles: characterization and pharmacokinetics in rats. J Pharm Sci. 2009 Apr;98(4):1577-86. PubMed PMID: 18752263; PubMed Central PMCID: PMC2649998.

20: Sauvageot CM, Weatherbee JL, Kesari S, Winters SE, Barnes J, Dellagatta J, Ramakrishna NR, Stiles CD, Kung AL, Kieran MW, Wen PY. Efficacy of the HSP90 inhibitor 17-AAG in human glioma cell lines and tumorigenic glioma stem cells. Neuro Oncol. 2009 Apr;11(2):109-21. Epub 2008 Aug 5. PubMed PMID: 18682579; PubMed Central PMCID: PMC2718982.

21: Rao R, Fiskus W, Yang Y, Lee P, Joshi R, Fernandez P, Mandawat A, Atadja P, Bradner JE, Bhalla K. HDAC6 inhibition enhances 17-AAG--mediated abrogation of hsp90 chaperone function in human leukemia cells. Blood. 2008 Sep 1;112(5):1886-93. Epub 2008 Jun 30. PubMed PMID: 18591380.

22: Jane EP, Pollack IF. The heat shock protein antagonist 17-AAG potentiates the activity of enzastaurin against malignant human glioma cells. Cancer Lett. 2008 Sep 8;268(1):46-55. Epub 2008 May 6. PubMed PMID: 18462865; PubMed Central PMCID: PMC2596131.

23: Babchia N, Calipel A, Mouriaux F, Faussat AM, Mascarelli F. 17-AAG and 17-DMAG-induced inhibition of cell proliferation through B-Raf downregulation in WT B-Raf-expressing uveal melanoma cell lines. Invest Ophthalmol Vis Sci. 2008 Jun;49(6):2348-56. Epub 2008 Feb 15. PubMed PMID: 18281615.

24: Modi S, Stopeck AT, Gordon MS, Mendelson D, Solit DB, Bagatell R, Ma W, Wheler J, Rosen N, Norton L, Cropp GF, Johnson RG, Hannah AL, Hudis CA. Combination of trastuzumab and tanespimycin (17-AAG, KOS-953) is safe and active in trastuzumab-refractory HER-2 overexpressing breast cancer: a phase I dose-escalation study. J Clin Oncol. 2007 Dec 1;25(34):5410-7. PubMed PMID: 18048823.

25: Daozhen C, Lu L, Min Y, Xinyu J, Ying H. Synthesis of (131)I-labeled-[(131)I]iodo-17-allylamino-17-demethoxy geldanamycin ([(131)I]iodo-17-AAG) and its biodistribution in mice. Cancer Biother Radiopharm. 2007 Oct;22(5):607-12. PubMed PMID: 17979563.

26: Yao Q, Weigel B, Kersey J. Synergism between etoposide and 17-AAG in leukemia cells: critical roles for Hsp90, FLT3, topoisomerase II, Chk1, and Rad51. Clin Cancer Res. 2007 Mar 1;13(5):1591-600. PubMed PMID: 17332306.

27: Saporita AJ, Ai J, Wang Z. The Hsp90 inhibitor, 17-AAG, prevents the ligand-independent nuclear localization of androgen receptor in refractory prostate cancer cells. Prostate. 2007 Apr 1;67(5):509-20. PubMed PMID: 17221841; PubMed Central PMCID: PMC2810394.

28: Waza M, Adachi H, Katsuno M, Minamiyama M, Tanaka F, Sobue G. Alleviating neurodegeneration by an anticancer agent: an Hsp90 inhibitor (17-AAG). Ann N Y Acad Sci. 2006 Nov;1086:21-34. Review. PubMed PMID: 17185503.

29: Georgakis GV, Li Y, Rassidakis GZ, Medeiros LJ, Younes A. The HSP90 inhibitor 17-AAG synergizes with doxorubicin and U0126 in anaplastic large cell lymphoma irrespective of ALK expression. Exp Hematol. 2006 Dec;34(12):1670-9. PubMed PMID: 17157164.

30: Georgakis GV, Li Y, Younes A. The heat shock protein 90 inhibitor 17-AAG induces cell cycle arrest and apoptosis in mantle cell lymphoma cell lines by depleting cyclin D1, Akt, Bid and activating caspase 9. Br J Haematol. 2006 Oct;135(1):68-71. Epub 2006 Aug 22. PubMed PMID: 16925576.

31: Duus J, Bahar HI, Venkataraman G, Ozpuyan F, Izban KF, Al-Masri H, Maududi T, Toor A, Alkan S. Analysis of expression of heat shock protein-90 (HSP90) and the effects of HSP90 inhibitor (17-AAG) in multiple myeloma. Leuk Lymphoma. 2006 Jul;47(7):1369-78. PubMed PMID: 16923571.

32: Premkumar DR, Arnold B, Pollack IF. Cooperative inhibitory effect of ZD1839 (Iressa) in combination with 17-AAG on glioma cell growth. Mol Carcinog. 2006 May;45(5):288-301. PubMed PMID: 16550610.

33: Niikura Y, Ohta S, Vandenbeldt KJ, Abdulle R, McEwen BF, Kitagawa K. 17-AAG, an Hsp90 inhibitor, causes kinetochore defects: a novel mechanism by which 17-AAG inhibits cell proliferation. Oncogene. 2006 Jul 13;25(30):4133-46. Epub 2006 Feb 27. PubMed PMID: 16501598.

34: Pelicano H, Carew JS, McQueen TJ, Andreeff M, Plunkett W, Keating MJ, Huang P. Targeting Hsp90 by 17-AAG in leukemia cells: mechanisms for synergistic and antagonistic drug combinations with arsenic trioxide and Ara-C. Leukemia. 2006 Apr;20(4):610-9. PubMed PMID: 16482209.

35: Zsebik B, Citri A, Isola J, Yarden Y, Szöllosi J, Vereb G. Hsp90 inhibitor 17-AAG reduces ErbB2 levels and inhibits proliferation of the trastuzumab resistant breast tumor cell line JIMT-1. Immunol Lett. 2006 Apr 15;104(1-2):146-55. Epub 2005 Dec 12. PubMed PMID: 16384610.

36: Konstantinopoulos PA, Papavassiliou AG. 17-AAG: mechanisms of antitumour activity. Expert Opin Investig Drugs. 2005 Dec;14(12):1471-4. PubMed PMID: 16307487.

37: Premkumar DR, Arnold B, Jane EP, Pollack IF. Synergistic interaction between 17-AAG and phosphatidylinositol 3-kinase inhibition in human malignant glioma cells. Mol Carcinog. 2006 Jan;45(1):47-59. PubMed PMID: 16267832.

38: Guo W, Reigan P, Siegel D, Zirrolli J, Gustafson D, Ross D. Formation of 17-allylamino-demethoxygeldanamycin (17-AAG) hydroquinone by NAD(P)H:quinone oxidoreductase 1: role of 17-AAG hydroquinone in heat shock protein 90 inhibition. Cancer Res. 2005 Nov 1;65(21):10006-15. PubMed PMID: 16267026.

39: Waza M, Adachi H, Katsuno M, Minamiyama M, Sang C, Tanaka F, Inukai A, Doyu M, Sobue G. 17-AAG, an Hsp90 inhibitor, ameliorates polyglutamine-mediated motor neuron degeneration. Nat Med. 2005 Oct;11(10):1088-95. Epub 2005 Sep 11. PubMed PMID: 16155577.

40: Radujkovic A, Schad M, Topaly J, Veldwijk MR, Laufs S, Schultheis BS, Jauch A, Melo JV, Fruehauf S, Zeller WJ. Synergistic activity of imatinib and 17-AAG in imatinib-resistant CML cells overexpressing BCR-ABL--Inhibition of P-glycoprotein function by 17-AAG. Leukemia. 2005 Jul;19(7):1198-206. PubMed PMID: 15902298.

41: Hawkins LM, Narendran A. The geldanamycin derivative 17-AAG decreases VEGF secretion and leukemia growth support by trisomy 8 myelodysplastic syndrome bone marrow stromal cells. Pediatr Hematol Oncol. 2005 Mar;22(2):115-25. PubMed PMID: 15804996.

42: Hawkins LM, Jayanthan AA, Narendran A. Effects of 17-allylamino-17-demethoxygeldanamycin (17-AAG) on pediatric acute lymphoblastic leukemia (ALL) with respect to Bcr-Abl status and imatinib mesylate sensitivity. Pediatr Res. 2005 Mar;57(3):430-7. Epub 2005 Jan 19. PubMed PMID: 15659698.

43: George P, Bali P, Annavarapu S, Scuto A, Fiskus W, Guo F, Sigua C, Sondarva G, Moscinski L, Atadja P, Bhalla K. Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3. Blood. 2005 Feb 15;105(4):1768-76. Epub 2004 Oct 28. PubMed PMID: 15514006.

44: Fumo G, Akin C, Metcalfe DD, Neckers L. 17-Allylamino-17-demethoxygeldanamycin (17-AAG) is effective in down-regulating mutated, constitutively activated KIT protein in human mast cells. Blood. 2004 Feb 1;103(3):1078-84. Epub 2003 Oct 9. PubMed PMID: 14551138.

45: Topaly J, Schad M, Laufs S, Melo JV, Zeller WJ, Fruehauf S. Cross-resistance of imatinib mesylate and 17-AAG in imatinib-resistant cells that overexpress BCR-ABL. Br J Haematol. 2003 May;121(4):672-3. PubMed PMID: 12752112.

46: Jia W, Yu C, Rahmani M, Krystal G, Sausville EA, Dent P, Grant S. Synergistic antileukemic interactions between 17-AAG and UCN-01 involve interruption of RAF/MEK- and AKT-related pathways. Blood. 2003 Sep 1;102(5):1824-32. Epub 2003 May 8. PubMed PMID: 12738674.

47: Nimmanapalli R, O'Bryan E, Kuhn D, Yamaguchi H, Wang HG, Bhalla KN. Regulation of 17-AAG-induced apoptosis: role of Bcl-2, Bcl-XL, and Bax downstream of 17-AAG-mediated down-regulation of Akt, Raf-1, and Src kinases. Blood. 2003 Jul 1;102(1):269-75. Epub 2003 Mar 6. PubMed PMID: 12623837.