XRK3F2 free base

XRK3F2 free base is a p62 (autophagy adaptor protein 1) ZZ domain inhibitor, exhibiting specificity for the p62-ZZ domain over other signaling domains of p62. It can block the action and upregulation of TNFα in bone marrow stromal cells and induce apoptosis in multiple myeloma cells. XRK3F2 free base is applicable in studies related to multiple myeloma bone disease, acute myeloid leukemia, and multiple myeloma.

XRK3F2 free base at a concentration of 5 μM, when co-cultured for 48 hours and followed by 4 days of osteogenic culture, can prevent the inhibition of Runx2 expression and the upregulation of Gfi1 in MC4 pre-osteoblastic cells induced by multiple myeloma (MM). Additionally, XRK3F2 restores alkaline phosphatase activity in these cells. Furthermore, at 5 μM over 48 hours, it can block the upregulation of Gfi1, inhibition of Runx2, and induction of IL6 in primary mouse bone marrow mesenchymal stem cells (BMSC) treated with MM1.S conditioned medium or a combination of TNFα and IL7. This compound also impedes the recruitment of GFI1 and HDAC1 to the Runx2-P1 promoter in MM-induced cells, maintaining H3K9ac modification in MC4 pre-osteoblastic cells. XRK3F2 free base, at doses ranging from 2.5-5 μM over 4 days, rescues the expression of Runx2, osteogenic target gene expression, and H3K9ac levels in MM-exposed MC4 pre-osteoblastic cells, reducing GFI1 binding to the Runx2-P1 promoter. Administering 5 μM for 5 days restores Runx2 mRNA expression during osteogenic differentiation in HD-hBMSC treated by MM. XRK3F2 also suppresses the viability of leukemia cells K562, HL-60, K562/A02, and HL60/ADR with IC50 values ranging from 6.41 to 8.76 μM when applied at concentrations of 0-20 μM for 72 hours. At 5 μM, it induces apoptosis in primary human acute myeloid leukemia CD34+ CD38− cells. Additionally, with a range of 0.1-10 μM over 48 hours, it can inhibit TNFα-induced differentiation of human CD116+ osteoclast (OCL) precursor cells. Lastly, at 10 μM, effective over 48 to 72 hours, XRK3F2 significantly impedes the proliferation of human MM cell lines, primary MM cells, and mouse 5TGM1-gfp cells through apoptosis, with an IC50 of 4.35 μM for 5TGM1 cells.

The XRK3F2 free base, administered via intraperitoneal injection at a dosage of 40 mg/kg once daily for 10 consecutive days, exhibits in vivo leukemia-inhibiting activity in PDX models, effectively reducing leukemia burden. Additionally, XRK3F2 free base (27, 40 mg/kg/day; intraperitoneal injection, administered for 5 consecutive days per week over 2 weeks) significantly induces new cortical bone formation specifically in the bone areas affected by multiple myeloma (MM) in immunocompetent models.