Development of Novel Dual Inhibitor of Chemokine Receptor 4 and Mcl-1 Against Multiple Myeloma

Multiple myeloma (MM) is a neoplastic plasma-cell disorder. This is characterized by clonal proliferation of malignant plasma cells in the bone-marrow (BM) microenvironment, monoclonal protein in blood or urine, and associated organ dysfunction. The treatment options approved by FDA are immune-modulatory agents, proteasome inhibitors, and autologous stem cell transplantation (ASCT). Unfortunately, MM remains uniformly fatal owing to intrinsic or acquired drug resistance and the median survival time is 3 to 5 years. Thus, there is a great need for novel strategies to combat MM. The intimate relationship of myeloma cells to BM microenvironment is “hallmark of myeloma”. The homing of MM cells to the BM, mediated by the chemokine stromal cell-derived factor-1α (SDF-1α) and its receptor CXCR4 has important functional sequelae. The BM microenvironment constituting cells secrete chemokines, cytokines, and growth factors such as interleukin 6 (IL6), vascular endothelial growth factor (VEGF), SDF-1α, and tumor necrosis factor α (TNFα) etc. These growth factors either secreted by MM or BM microenvironment cells (e.g. stromal cells) contribute in activation of several signaling pathways including nuclear factor-κB (NF-κB); phosphatidylinositol 3-kinase (PI3K)-Akt; Ras-Raf-MAPK kinase (MEK)-extracellular signal regulated kinase (ERK); and the Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3). Activation of these pathways has been associated with increased expression of several anti-apoptotic proteins such as Bcl-2, Bcl-xL, Mcl-1, and XIAP. Collectively, these discoveries highlight that interaction of MM cells to BM microenvironment not only promote growth, survival and migration of MM cells, but also confer resistance to conventional chemotherapy. We hypothesized that an agent capable of inhibiting the migration of myeloma cells to bone marrow and suppressing the expression of survival protein Mcl-1 would be a better option for MM treatment.We have synthesized a novel dual inhibitor of CXCR4 and Mcl-1. Our data suggests that this molecule inhibits the expression of CXCR4 and Mcl-1 and survival of MM cells