Abstract 4477: The development of a small molecule dual inhibitor of CXCR4 and Mcl-1 to target bortezomib resistant and stem-like cells in multiple myeloma

Abstract Multiple myeloma (MM) is a malignant plasma-cell illness defined by clonal growth of malignant plasma cells within the bone marrow (BM) microenvironment. Despite the availability of many therapeutic alternatives, MM remains consistently lethal, demanding the development of novel techniques. The intimate relationship between myeloma cells and the BM microenvironment is a distinguishing hallmark of MM. The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 enhance the homing of MM cells to the BM, which has important functional implications. The BM microenvironment secretes a variety of hormones and cytokines that activate several signaling pathways, resulting in enhanced production of the anti-apoptotic Mcl-1 protein, boosting the proliferation, survival, and migration of MM cells and conferring resistance to standard chemotherapy. As a result, we created GA-A, a hybrid molecule in which we coupled an aralkyl carboxylic acid moiety, known to preferentially inhibit Mcl-1, to gambogic acid, which has previously been demonstrated to inhibit CXCR4 in MM. Our western blot has shown that this unique hybrid compound successfully suppressed CXCR4 and Mcl-1. Interestingly, using qPCR we found that CXCR4 was observed to be higher expressed in CD138- versus CD138+ cells, while GA-A inhibited CXCR4 in both subpopulations. In addition, using annexin-V flow cytometry staining we found that GA-A increased the apoptotic effect of bortezomib in MM stem-like cells while inhibiting the viability of bortezomib resistant cells. Using human cytokine array we found that GA-A activates some of proinflammatory cytokines that can activate the immune system such as GM-CSF, IFN gamma, IL-2 and IL-12. In summary, our findings indicate the successful creation of a novel dual CXCR4-Mcl1 inhibitor that demonstrates efficacy against the stem cell-like population and bortezomib resistant cells and enhances the effectiveness of bortezomib. Citation Format: Weam Othman Elbezanti, Omar S. Al-Odat, Subash C. Jonnalagadda, Tulin Budak-Alpdogan, Manoj K. Pandey. The development of a small molecule dual inhibitor of CXCR4 and Mcl-1 to target bortezomib resistant and stem-like cells in multiple myeloma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4477.