p62 (sequestosome 1) serves as a signaling hub in BMSC (bone marrow stromal cells) for the formation of signaling complexes involved in the BMSC-induced increase in osteoclastogenesis and MM cell growth characteristic of MMBD, including NFκB, p38MAPK, and JNK, and the ZZ-domain of p62 (p62-ZZ) is required for BMSC enhancement of MMBD[1]. XRK3F2, a novel small molecule inhibitor the p62-ZZ domain of signaling, which blocks TNFα and MM activation of downstream signaling from the p62-signaling hubblunted MM (Multiple myeloma)-induced Runx2 suppression in vitro, and induced new bone formation and remodeling in the presence of tumor in vivo. In addition, XRK3F2 also directly decreased osteoclast (OCL) formation. Further, XRK3F2 directly inhibited cell growth of primary CD138+ MM cells and human MM cell lines in vitro, without negatively affecting the growth of BMSC[2]. In a vitro dtudy, primary MM cells, human MM cell lines, or murine 5TGM1-gfp cells were incubated with XRK3F2 for 48h or 72h in concentrations of 10 mg/ml for 0 – 30 mins. It demonstrated that XRK3F2 blocks TNFα-induced signaling processes in MM patient BMSC and MM cells. The IC50 of XRK3F2 for 5TGM1 cells was 4.35 µM, and 4.6 µM for the human MM1.S cell line. 1 × 105 5TGM1-gfp cells in logarithmic phase growth were inoculated into one tibia (IT) of C57BL/KaLwRij mice and the mice were treated with either XRK3F2 (27 mg/kg/day or 40 mg/kg/day) or vehicle. Six of 17 XRK3F2-treated and 1 vehicle-treated animal demonstrated a marked periosteal reaction on x-ray, suggesting new bone formation along the tibia, which showed that XRK3F2 induced dramatic, local new bone formation in bones bearing MM in vivo[2].
作用机制
XRK3F2 selective blocking of the p62-ZZ domain-signaling module, may also influence cytoplasmicnuclear shuttling and/or Ajuba-dependent binding of GFI1 to the Runx2 promoter[1].
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