Ralimetinib

Ralimetinib is an ATP-competitive p38α and p38β MAPK inhibitor with an IC₅₀ of 5.3 nmol/L against human p38α and an IC₅₀ of 3.2 nmol/L against human p38β. Ralimetinib slows tumor growth in preclinical in vivo cancer models, exhibits oral bioavailability in mice, and achieves sustained target inhibition for 4 to 8 h. Ralimetinib is applicable for research on melanoma, non-small cell lung cancer, ovarian cancer, glioma, multiple myeloma, breast cancer, renal cancer, and head and neck squamous cell carcinoma^[1][2]. IC50 & Target:IC50: 5.3 nM (p38 MAPK α), 3.2 nM (p38 MAPK β)^[1] In Vitro:LY2228820 (1 nmol/L-20 μmol/L; 2 h pre-incubation, 30 min anisomycin stimulation) potently inhibits p38 pathway-mediated MK2 phosphorylation in anisomycin-stimulated RAW264.7 macrophages with an IC₅₀ of 35.3 nmol/L^[1].
LY2228820 (1 nmol/L-20 μmol/L; 0.5 h pre-incubation, 2 h LPS/IFN-γ stimulation) potently inhibits LPS/IFN-γ-induced TNF-α secretion in mouse peritoneal macrophages with an IC₅₀ of 6.3 nmol/L^[1].
LY2228820 (9.8 nmol/L-10 μmol/L; 1 h pre-incubation, 45 min anisomycin stimulation) selectively inhibits p38 pathway-mediated MK2 phosphorylation in anisomycin-stimulated HeLa cells at 9.8 nmol/L, with no off-target effects on JNK, ERK1/2, or their downstream substrates up to 10 μmol/L^[1].
LY2228820 (1 nmol/L-20 μmol/L; 30 min pre-incubation, 72 h LPS stimulation) inhibits LPS-induced CXCL8 secretion in A549 non-small cell lung cancer cells with an IC₅₀ of 144.9 nmol/L^[1].
LY2228820 inhibits p38 pathway-mediated MK2 phosphorylation in human peripheral blood mononuclear cells ex vivo with an IC₅₀ of 0.12 μmol/L^[1].
Ralimetinib (1.6 μM; two 72 h treatment intervals) induces apoptosis (19.12% Annexin positivity, 14.51% sub-G₁ phase) and modulates cell cycle distribution in SCC-25 cells, and enhances TGF-beta-1-induced Annexin positivity (24.23%) while causing G₂/S arrest in TGF-beta-1-pretreated SCC-25 cells^[2].
Ralimetinib (1.6 μM; two 72 h treatment intervals) inhibits phosphorylation of the p38 MAPK downstream target ATF2 (Thr69/71) in SCC-25 cells, with maximal inhibition observed in TGF-beta-1-pretreated cells^[2]. In Vivo:Ralimetinib (0.1-30 mg/kg; p.o.; single dose) dose-dependently inhibits tumor phospho-MK2 in C57BL/6 mice bearing B16-F10 melanoma, with a TED₅₀ of 1.95 mg/kg and >40% target inhibition maintained for 4 to 8 hours after a single 10 mg/kg oral dose^[1].
Ralimetinib (20 mg/kg; p.o.; 3 times a day; continuous or intermittent schedule) administered at 20 mg/kg three times daily via continuous or intermittent oral schedules produces significant tumor growth delay in athymic nude mice bearing A549 non-small cell lung cancer xenografts^[1].
Ralimetinib (10 mg/kg; p.o.; 3 times a day; 4 days on/3 days off; 3 weeks) administered at 10 mg/kg three times daily on a 4 days on/3 days off oral schedule achieves 72% tumor growth inhibition in CD1 nu/nu mice bearing A-2780 ovarian cancer xenografts^[1].
Ralimetinib (14.7 mg/kg; p.o.; twice a day; continuous schedule) administered at 14.7 mg/kg twice daily via continuous oral schedule completely attenuates tumor growth in athymic nude mice bearing U-87MG glioma xenografts^[1].
Ralimetinib (p.o.) administered via oral schedule produces 60% tumor growth inhibition in athymic nude mice bearing MDA-MB-468 breast cancer xenografts^[1].
Ralimetinib (p.o.) administered via oral schedule produces 42% tumor growth inhibition in irradiated CB-17 SCID mice bearing OPM-2 multiple myeloma xenografts^[1].
Ralimetinib (30 mg/kg; p.o.; 3 times a day; 4 days on/3 days off; 14 consecutive days) administered at 30 mg/kg three times daily on a 4 days on/3 days off oral schedule reduces lung metastases by 57% in nude mice with B16-F10 melanoma tail vein metastases^[1].
Ralimetinib (10-30 mg/kg; p.o.; 3 times a day; 3 days on/3 days off; 3 weeks) administered at 10 mg/kg or 30 mg/kg three times daily on a 3 days on/3 days off oral schedule produces 50% to 51% tumor growth inhibition in female athymic nude mice with orthotopic intraperitoneal SK-OV-3 ovarian cancer xenografts^[1].
Ralimetinib (30 mg/kg; p.o.; 3 times a day; continuous; 3 weeks) administered at 30 mg/kg three times daily via continuous oral schedule produces a 44% decrease in tumor luminescence and 35% reduction in tumor weight in female athymic nude mice with orthotopic renal capsule 786-O renal carcinoma xenografts^[1].