(2R)-1-{4-[(1aR,6r,10bS)-1,1-Difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-yl]piperazin-1-yl}-3-(quinolin-5-yloxy)propan-2-ol

Uses

Treatment of multidrug resistance (modulator of Pgp resistance).

Definition

ChEBI: LSM-5782 is a carbopolycyclic compound.

Biological Activity

zosuquidar (ly335979) 3hcl is a novel and potent modulator of p-glycoprotein (p-gp) [1]. p-gp is wildly expressed in brain, liver, small intestine and tumor cells and acts as an efflux pump responsible for multidrug resistance in tumor cells. overexpression of pgp in tumors results in multidrug resistance (mdr) to structurally unrelated oncolytics [2].

Biochem/physiol Actions

Zosuqidar is a potent inhibitor of P-glycoprotein (P-gp, MDR1) a transporter protein that is a key modulator of cellular drug efflux. Zosuquidar sensitizes AML, and other cancer cell lines to cytotoxic drugs.

in vitro

in cem/vlb100 cells, ly335979 treatment (0.1 μm) fully restored the sensitivity to vinblastine, doxorubicin (dox), etoposide, and taxol. in cem/vlb100 plasma membranes, ly335979 blocked [3h]azidopinephotoaffinity labeling of the m(r) approximately 170,000 pgp and competitively inhibited equilibrium binding of [3h]vinblastine to pgp with the ki value of approximately 0.06 μm [3]. in all p-gp-expressing leukemia cell linesincluding k562/hht40, k562/hht90, k562/dox and hl60/dnr, zosuquidar completely or partially restored drug sensitivity. in primary aml blasts with active p-gp, zosuquidar enhanced the cytotoxicity of anthracyclines (daunorubicin, idarubicin, mitoxantrone) and gemtuzumabozogamicin (mylotarg)[4].

in vivo

in mice bearing p388/adr murine leukemia cells,treatment with ly335979 in combination with dox or etoposide significantly increased in life span with no apparent alteration of pharmacokinetics. in a mdr human non-small cell lung carcinoma nude mouse xenograft model, ly335979 enhanced the antitumor activity of taxol [3].

References

[1] cripe l d, uno h, paietta e m, et al. 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[j]. blood, 2010, 116(20): 4077-4085.
[2] chaudhary p m, roninson i b. expression and activity of p-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells[j]. cell, 1991, 66(1): 85-94.
[3] dantzig a h, shepard r l, cao j, et al. reversal of p-glycoprotein-mediated multidrug resistance by a potent cyclopropyldibenzosuberane modulator, ly335979[j]. cancer research, 1996, 56(18): 4171-4179.
[3] tang r, faussat a m, perrot j y, et al. zosuquidar restores drug sensitivity in p-glycoprotein expressing acute myeloid leukemia (aml)[j]. bmc cancer, 2008, 8(1): 1.
[4] morschhauser f, zinzani p l, burgess m, et al. 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[j]. leukemia & lymphoma, 2007, 48(4): 708-715.
[5] lê l h, moore m j, siu l l, et al. phase i study of the multidrug resistance inhibitor zosuquidar administered in combination with vinorelbine in patients with advanced solid tumours[j]. cancer chemotherapy and pharmacology, 2005, 56(2): 154-160.