The chemokine receptor CXCR4 and its ligand CXCL12 are involved in the progression and dissemination of a diverse number of solid and hematological malignancies. Binding CXCL12 to CXCR4 activates a variety of intracellular signal transduction pathways that regulate cell chemotaxis, adhesion, survival, proliferation, and apoptosis[3]. CXCR4 plays an important role in the retention of stem cells within the bone marrow[4]. BKT140 (4F-benzoyl-TN14003), a novel CXCR4 antagonist, binds and inhibits the CXCR4 chemokine receptor with high affinity, showing an IC50 of ∼1 nM. Moreover, BKT140 hinders the cell migration stimulated by CXCL12 within IC50 values of 0.5 to 2.5 nM, suggesting a high mobilization capacity[4]. BKT140 displays selective toxicity toward AML and MM cells. Treatment with BKT140 can overcome IL-6 dependent proliferation and survival of ARH77 MM cells. BKT140 specifically triggers CXCR4-dependent cell death and stimulates apoptotic cell death in leukemia and MM cells[3]. Subcutaneous injections of BKT140 significantly reduce, in a dose-dependent manner, the growth of human acute myeloid leukemia and multiple myeloma xenografts. Tumors from animals treated with Motixafortide (BKT140) are smaller in size and weights and had larger necrotic areas and higher apoptotic scores[3]. BKT140 was well tolerated at all concentrations, and none of the patients developed grade 3 and 4 toxicity. A single administration of BKT140 at the highest dose, 0.9 mg/kg, resulted in a robust mobilization and collection of CD34 (+) cells (20.6 ± 6.9 × 106/kg), which were obtained through a single apheresis[4].
搜索
