LY2228820 dimesylate

LY2228820 dimesylate (Ralimetinib) is a potent, selective, orally available inhibitor p38 MAPK with IC50 of 5.3 and 3.2 nM for p38α and p38β, respectively; potently and selectively inhibits phosphorylation of MK2 (Thr334) in anisomycin-stimulated HeLa cells and mouse RAW264.7 macrophages (IC50=35.3 nM), with no changes in phosphorylation of p38α MAPK, JNK, ERK1/2, c-Jun, ATF2, or c-Myc; also reduces TNF-α secretion by LPS/IFN-γ–stimulated macrophages with IC50 of 6.3 nM; produces significant tumor growth delay in multiple in vivo cancer models (melanoma, non-small cell lung cancer, ovarian, glioma, myeloma, breast) .Ovarian Cancer Phase 2 Clinical (In Vitro) :Ralimetinib dimesylate inhibits p38α, as well as the level of phosphoMAPKAPK-2 (pMK2) in RAW 264.7 cells, with IC50 values of 7 nM and 34.3 nM, respectively. Furthermore, Ralimetinib dimesylate inhibits lipopolysaccharide (LPS) -induced TNFα formation in murine peritoneal macrophages, with IC50 of 5.2 nM. In multiple myeloma (MM) cells, including INA6, RPMI-8226, U266, and RPMI-Dox40, Ralimetinib dimesylate (LY2228820) (200 nM-800 nM) significantly blocks p38MAPK signaling, as revealed by its inhibition on phosphorylation of HSP27, a downstream target of p38MAPK, without affecting the expression level of HSP27. Ralimetinib dimesylate (200 nM-400 nM) enhances bortezomib-induced cytotoxicity and apoptosis, but Ralimetinib dimesylate alone doesn't inhibit the growth of MM.1S cells. Ralimetinib dimesylate (200 nM-800 nM) also inhibits secretion of IL-6 and MIP-1α in long-term BM stromal cells (LT-BMSCs), BM mononuclear cells (BMMNCs), peripheral blood (PB) CD138+, CD138- or PB CD14+ cells. Ralimetinib dimesylate (400 nM-800 nM) also blocks osteoclastogenesis from CD14+ cells. (In Vivo) :In LPS-induced mice, Ralimetinib dimesylate effectively inhibits the formation of TNFα with a threshold minimum 50% effective dose (TMED50) less than 1 mg/kg. In a rat model of collagen-inducedarthritis (CIA), Ralimetinib dimesylate displays potent effects on paw swelling, bone erosion, and cartilage destruction, with a threshold minimum 50% effective dose (TMED50) of 1.5 mg/kg. Ralimetinib dimesylate inhibits tumor phospho-MK2 in a dose-dependent manner (TED50=1.95 mg/kg, TED70=11.17 mg/kg) in mice implanted with B16-F10 melanoma. Ralimetinib dimesylate inhibits MK2 phosphorylation: mouse in vivo TED50=1.01 mg/kg (compound exposure approximately 100 nM) and human ex vivo IC50=0.12 μM with either mouse or human PBMC.