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VX-710 or (S)-N-[2-Oxo-2-(3,4,5-trimethoxyphenyl)acetyl]-plperidine-2-carboxyllc acid 1,7-bls(3-pyridyl)-4-heptyl ester, a novel non-macrocyclic ligand of the FK506-binding protein FKBP12, was evaluated for Its ability to reverse P-glycoprotein-mediated multidrug resistance In vitro. VX-710 at 0.5–5 μM restored sensitivity of a variety of multi-drug resistant cells to the cytotoxic action of doxorubicin, vincristine, etoposide or paclltaxel, Including drug-selected human myeloma and epithelial carcinoma cells, and human MDR1 cDNA-transfected mouse leukemia and fibroblast cells. Uptake experiments showed that VX-710 at 0.5–2.5 μM fully restored intracellular accumulation of [14C]doxorubicin In multidrug resistant cells, suggesting that VX-710 Inhibits the drug efflux activity of P-glyco-protein. VX-710 effectively inhibited photoaffinity labeling of P-glycoprotein by [3H]azidopine or [125I]iodoaryl azido-prazosin with EC50 values of 0.75 and 0.55 μM. Moreover, P-glycoprotein was specifically labeled by a tritiated photo-affinity analog of VX-710 and unlabeled VX-710 inhibited analog binding with an EC50 of 0.75 μM. VX-710 also stimulated the vanadate-inhibitable P-glycoprotein ATPase activity 2− to 3-fold In a concentration-dependent manner with an apparent ka, of 0.1 μM. These data indicate that a direct, high-affinity Interaction of VX-710 with P-glycoprotein prevents efflux of cytotoxic drugs by the MDR1 gene product In multidrug resistant tumor cells.