Ralimetinib dimesylate

Ralimetinib dimesylate (LY2228820 dimesylate) is a selective, ATP-competitive inhibitor of p38 MAPK α/β with IC₅₀s of 5.3 and 3.2 nM, respectively. Ralimetinib (LY2228820) selectively inhibits phosphorylation of MK2 (Thr334), with no effect on phosphorylation of p38a MAPK, JNK, ERK1/2, c-Jun, ATF2, or c-Myc. IC50 & Target: IC50: 5.3 nM (p38 MAPK α), 3.2 nM (p38 MAPK β)^[3] 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^[1]. 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^[2]. 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^[1]. 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^[3].