FK866

FK866 (APO866, Daporinad) effectively inhibits nicotinamide phosphoribosyltransferase (NMPRTase) with IC50 of 0.09 nM in a cell-free assay. Phase 1/2.(In Vitro):Nampt inhibition with (E)-Daporinad (FK866) induces significant NAD+ intracellular reduction and selectively kills MM cells. (E)-Daporinad (FK866)-induced cell death is associated with inhibition of Nampt activity, rather than protein expression, and higher NAD+ baseline levels in MM cells than normal PBMCs confer (E)-Daporinad (FK866) sensitivity. (E)-Daporinad (FK866) abrogates the survival advantage conferred by the bone marrow microenvironment. (E)-Daporinad (FK866) prevents the [Ca2+]i increase induced by different mitogens and reduces the Ca2+ content of TG-responsive Ca2+ stores in Jurkat and in activated PBLs. (E)-Daporinad (FK866) reduces the Ca2+ content of TG-responsive Ca2+ stores in Jurkat cells but not in Bcl2-Jurkat cells. Inhibition of NAMPT by (E)-Daporinad (FK866), or inhibition of SIRT by nicotinamide decreases proliferation and triggered death of 293T cells involving the p53 acetylation pathway.(In Vivo):(E)-Daporinad (FK866) (30 mg/kg, i.p.) decreases the tumor burden in CB17-SCID mice, and the tumor tissue demonstrates a significant decrease in ERK phosphorylation and proteolytic cleavage of LC3.