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 Zosuquidar trihydrochloride

Description of Zosuquidar: Zosuquidar  is a potent P-glycoprotein inhibitor, which binds with high affinity to P-glycoprotein and inhibits P-glycoprotein-mediated multidrug resistance (MDR). P-glycoprotein, encoded by the MDR-1 gene, is a member of the ATP-binding cassette superfamily of transmembrane transporters and prevents the intracellular accumulation of many natural product-derived cytotoxic agents. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:   Roche Bioscience (Originator), Eli Lilly and Company (Licensee).

Zosuquidar is currently under development. It is now in "Phase 3" of clinical tests in the United States. Its action mechanism consists of the inhibition of P-glycoproteins; other drugs with this mechanism include tariquidar and laniquidar. P-glycoproteins are proteins which convert the energy derived from the hydrolysis of ATP to structural changes in protein molecules, in order to perform coupling, thus discharging medicine from cells. If P-glycoprotein coded with the MDR1 gene manifests itself in cancer cells, it discharges much of the antineoplastic drugs from the cells, making cancer cells medicine tolerant, and rendering antineoplastic drugs ineffective. This protein also manifests itself in normal organs not affected by the cancer (such as the liver, small intestine, and skin cells in blood vessels of the brain), and participates in the transportation of medicine. The compound Zosuquidar inhibits this P-glycoprotein, causing the cancer cells to lose their medicine tolerance, and making antineoplastic drugs effective (The above information was from:http://en.wikipedia.org/wiki/Zosuquidar).

Clinicial trials: Clinical report published in 2010 showed that  zosuquidar did not improve outcome in older acute myeloid leukemia, in part, because of the presence P-gp independent mechanisms of resistance. (Blood. 2010 Nov 18;116(20):4077-85.)

1: Infed N, Smits SH, Dittrich T, Braun M, Driessen AJ, Hanekop N, Schmitt L. Analysis of the inhibition potential of zosuquidar derivatives on selected bacterial and fungal ABC transporters. Mol Membr Biol. 2013 Mar;30(2):217-27. doi: 10.3109/09687688.2012.758876. PubMed PMID: 23356389.

2: Abu Ajaj K, Graeser R, Kratz F. Zosuquidar and an albumin-binding prodrug of zosuquidar reverse multidrug resistance in breast cancer cells of doxorubicin and an albumin-binding prodrug of doxorubicin. Breast Cancer Res Treat. 2012 Jul;134(1):117-29. doi: 10.1007/s10549-011-1937-9. Epub 2012 Jan 8. PubMed PMID: 22228402.

3: Cripe LD, Uno H, Paietta EM, Litzow MR, Ketterling RP, Bennett JM, Rowe JM, Lazarus HM, Luger S, Tallman MS. Zosuquidar, a novel modulator of P-glycoprotein, does not improve the outcome of older patients with newly diagnosed acute myeloid leukemia: a randomized, placebo-controlled trial of the Eastern Cooperative Oncology Group 3999. Blood. 2010 Nov 18;116(20):4077-85. doi: 10.1182/blood-2010-04-277269. Epub 2010 Aug 17. PubMed PMID: 20716770; PubMed Central PMCID: PMC2993615.

4: Ruff P, Vorobiof DA, Jordaan JP, Demetriou GS, Moodley SD, Nosworthy AL, Werner ID, Raats J, Burgess LJ. A randomized, placebo-controlled, double-blind phase 2 study of docetaxel compared to docetaxel plus zosuquidar (LY335979) in women with metastatic or locally recurrent breast cancer who have received one prior chemotherapy regimen. Cancer Chemother Pharmacol. 2009 Sep;64(4):763-8. doi: 10.1007/s00280-009-0925-9. Epub 2009 Feb 25. PubMed PMID: 19241078.

5: Lancet JE, Baer MR, Duran GE, List AF, Fielding R, Marcelletti JF, Multani PS, Sikic BI. A phase I trial of continuous infusion of the multidrug resistance inhibitor zosuquidar with daunorubicin and cytarabine in acute myeloid leukemia. Leuk Res. 2009 Aug;33(8):1055-61. doi: 10.1016/j.leukres.2008.09.015. Epub 2008 Dec 23. PubMed PMID: 19108889.

6: Marcelletti JF, Multani PS, Lancet JE, Baer MR, Sikic BI. Leukemic blast and natural killer cell P-glycoprotein function and inhibition in a clinical trial of zosuquidar infusion in acute myeloid leukemia. Leuk Res. 2009 Jun;33(6):769-74. doi: 10.1016/j.leukres.2008.09.020. Epub 2008 Oct 30. PubMed PMID: 18976810.

7: Tang R, Faussat AM, Perrot JY, Marjanovic Z, Cohen S, Storme T, Morjani H, Legrand O, Marie JP. Zosuquidar restores drug sensitivity in P-glycoprotein expressing acute myeloid leukemia (AML). BMC Cancer. 2008 Feb 13;8:51. doi: 10.1186/1471-2407-8-51. PubMed PMID: 18271955; PubMed Central PMCID: PMC2258302.

8: Morschhauser F, Zinzani PL, Burgess M, Sloots L, Bouafia F, Dumontet C. Phase I/II trial of a P-glycoprotein inhibitor, Zosuquidar.3HCl trihydrochloride (LY335979), given orally in combination with the CHOP regimen in patients with non-Hodgkin's lymphoma. Leuk Lymphoma. 2007 Apr;48(4):708-15. PubMed PMID: 17454628.

9: Bihorel S, Camenisch G, Lemaire M, Scherrmann JM. Modulation of the brain distribution of imatinib and its metabolites in mice by valspodar, zosuquidar and elacridar. Pharm Res. 2007 Sep;24(9):1720-8. Epub 2007 Mar 23. PubMed PMID: 17380257.

10: Anderson BD, May MJ, Jordan S, Song L, Roberts MJ, Leggas M. Dependence of nelfinavir brain uptake on dose and tissue concentrations of the selective P-glycoprotein inhibitor zosuquidar in rats. Drug Metab Dispos. 2006 Apr;34(4):653-9. Epub 2006 Jan 24. PubMed PMID: 16434546.

11: Lê LH, Moore MJ, Siu LL, Oza AM, MacLean M, Fisher B, Chaudhary A, de Alwis DP, Slapak C, Seymour L. Phase I study of the multidrug resistance inhibitor zosuquidar administered in combination with vinorelbine in patients with advanced solid tumours. Cancer Chemother Pharmacol. 2005 Aug;56(2):154-60. Epub 2005 Apr 5. PubMed PMID: 15809877.

12: Fracasso PM, Goldstein LJ, de Alwis DP, Rader JS, Arquette MA, Goodner SA, Wright LP, Fears CL, Gazak RJ, Andre VA, Burgess MF, Slapak CA, Schellens JH. Phase I study of docetaxel in combination with the P-glycoprotein inhibitor, zosuquidar, in resistant malignancies. Clin Cancer Res. 2004 Nov 1;10(21):7220-8. PubMed PMID: 15534095.

13: Gerrard G, Payne E, Baker RJ, Jones DT, Potter M, Prentice HG, Ethell M, McCullough H, Burgess M, Mehta AB, Ganeshaguru K. Clinical effects and P-glycoprotein inhibition in patients with acute myeloid leukemia treated with zosuquidar trihydrochloride, daunorubicin and cytarabine. Haematologica. 2004 Jul;89(7):782-90. PubMed PMID: 15257929.

14: Sandler A, Gordon M, De Alwis DP, Pouliquen I, Green L, Marder P, Chaudhary A, Fife K, Battiato L, Sweeney C, Jordan C, Burgess M, Slapak CA. A Phase I trial of a potent P-glycoprotein inhibitor, zosuquidar trihydrochloride (LY335979), administered intravenously in combination with doxorubicin in patients with advanced malignancy. Clin Cancer Res. 2004 May 15;10(10):3265-72. PubMed PMID: 15161679.

15: Callies S, de Alwis DP, Mehta A, Burgess M, Aarons L. Population pharmacokinetic model for daunorubicin and daunorubicinol coadministered with zosuquidar.3HCl (LY335979). Cancer Chemother Pharmacol. 2004 Jul;54(1):39-48. Epub 2004 Mar 24. PubMed PMID: 15045528.

16: Kemper EM, Ouwehand M, Beijnen JH, van Tellingen O. Bioanalysis of zosuquidar trihydrochloride (LY335979) in small volumes of human and murine plasma by ion-pairing reversed-phase high-performance liquid chromatography. J Chromatogr B Analyt Technol Biomed Life Sci. 2003 Dec 5;798(1):63-8. PubMed PMID: 14630360.

17: Kemper EM, Cleypool C, Boogerd W, Beijnen JH, van Tellingen O. The influence of the P-glycoprotein inhibitor zosuquidar trihydrochloride (LY335979) on the brain penetration of paclitaxel in mice. Cancer Chemother Pharmacol. 2004 Feb;53(2):173-8. Epub 2003 Nov 7. PubMed PMID: 14605863.

18: Callies S, de Alwis DP, Harris A, Vasey P, Beijnen JH, Schellens JH, Burgess M, Aarons L. A population pharmacokinetic model for paclitaxel in the presence of a novel P-gp modulator, Zosuquidar Trihydrochloride (LY335979). Br J Clin Pharmacol. 2003 Jul;56(1):46-56. Erratum in: Br J Clin Pharmacol. 2003 Oct;56(4):463. PubMed PMID: 12848775; PubMed Central PMCID: PMC1884334.

19: Callies S, de Alwis DP, Wright JG, Sandler A, Burgess M, Aarons L. A population pharmacokinetic model for doxorubicin and doxorubicinol in the presence of a novel MDR modulator, zosuquidar trihydrochloride (LY335979). Cancer Chemother Pharmacol. 2003 Feb;51(2):107-18. Epub 2003 Jan 10. PubMed PMID: 12647011.

20: Rubin EH, de Alwis DP, Pouliquen I, Green L, Marder P, Lin Y, Musanti R, Grospe SL, Smith SL, Toppmeyer DL, Much J, Kane M, Chaudhary A, Jordan C, Burgess M, Slapak CA. A phase I trial of a potent P-glycoprotein inhibitor, Zosuquidar.3HCl trihydrochloride (LY335979), administered orally in combination with doxorubicin in patients with advanced malignancies. Clin Cancer Res. 2002 Dec;8(12):3710-7. PubMed PMID: 12473580.