LY2784544

LY2784544 (Gandotinib) is a potent, selective and ATP-competitive inhibitor of JAK2V617F, effectively inhibits JAK2V617F-driven signaling and cell proliferation in Ba/F3 cells (IC50=20 and 55 nM, respectively) ; inhibits JAK2 and JAK3 in biochemical assays with IC50 of 3 nM and 48 nM, respectively; LY2784544 is much less potent at inhibiting IL-3-stimulated wild-type JAK2-mediated signaling and cell proliferation (IC50=1183 and 1309 nM, respectively) ; effectively inhibits STAT5 phosphorylation in Ba/F3-JAK2V617F-GFP ascitic tumor cells (TED50=12.7 mg/kg) and significantly reduces Ba/F3-JAK2V617F-GFP tumor burden in the JAK2V617F-induced MPN model; also is a potent GPR39 agonist with pEC50 of 9.36 (at 316 uM ZnCl2) .Blood Cancer Phase 2 Clinical (In Vitro) :Gandotinib (LY2784544), a potent, selective and ATP-competitive inhibitor of janus kinase 2 (JAK2) tyrosine kinase. LY2784544 effectively inhibits JAK2V617F-driven signaling and cell proliferation in Ba/F3 cells (IC50=20 and 55 nM, respectively) . In comparison, Gandotinib (LY2784544) is much less potent at inhibiting interleukin-3-stimulated wild-type JAK2-mediated signaling and cell proliferation (IC50=1183 and 1309 nM, respectively) . Gandotinib (LY2784544) potently inhibits the JAK2V617F signaling (IC50=20 nM) but, remarkably, shows very minimal activity against the IL-3-activated wild-type JAK2 signaling with an IC50 of 1183 nM. LY2784544 inhibits the proliferation of JAK2V617F-expressing cells (IC50=55 nM) and is markedly less potent as an inhibitor of the proliferation of IL-3-stimulated wild-type JAK2 expressing Ba/F3 cells (IC50=1309 nM) . Gandotinib (LY2784544) is potent in the cell-based TF-1 JAK2 assay (IC50=45 nM) and had the desired threshold selectivity in the NK-92 JAK3/JAK1 heterodimer assay (942 nM) . (In Vivo) :Gandotinib (LY2784544) effectively inhibits STAT5 phosphorylation in Ba/F3-JAK2V617F-GFP (green fluorescent protein) ascitic tumor cells (TED50=12.7 mg/kg) and significantly reduces (P<0.05) Ba/F3-JAK2V617F-GFP tumor burden in the JAK2V617F-induced MPN model (TED50=13.7 mg/kg, twice daily) .