Abstract 3952: A novel Mcl-1 inhibitor induces cells death in a caspase-dependent manner and increases the efficacies of Venetoclax and ABT-737 in multiple myeloma cells

Abstract Multiple myeloma (MM) is a deadly malignancy of the blood, characterized by the uncontrolled proliferation of plasma cells. MM is challenging to diagnose and treat, accounting for approximately 12% of hematologic malignancies. The overexpression of anti-apoptotic proteins, particularly Myeloid cell leukemia 1 (Mcl-1), play a significant role in the pathogenesis of MM. The overexpression of Mcl-1 is associated with acquired resistance and poor prognosis. Thus, inhibition of the Mcl-1 protein is an attractive therapeutic strategy against myeloma cells. We synthesized and developed a novel Mcl-1 inhibitor, KS18. The preclinical testing of this novel agent is investigated in MM cell lines. Through docking studies, we predicted that KS18 interacts with Mcl-1. KS18 down-regulates the expression of Mcl-1 in MM cells in a dose- and time-dependent manner. Suppression of Mcl-1 expression by KS18 correlated with activation of caspases, PARP- cleavage, and apoptosis. However, this molecule had no effect on the expression of Bcl-2 and Bcl-xL proteins. Importantly, KS18 markedly enhances the efficacies of Venetoclax and ABT-737 in MM cells. Our results propose that targeting Mcl-1 by KS18 may represent a new viable strategy for MM treatment. Citation Format: Omar S. Al-Odat, Rahul S. Tripathi, Sandeep K. Srivastava, Krishne Gowda, Shantu G. Amin, Tulin Budak-Alpdogan, Subash C. Jonnalagadda, Manoj K. Pandey. A novel Mcl-1 inhibitor induces cells death in a caspase-dependent manner and increases the efficacies of Venetoclax and ABT-737 in multiple myeloma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3952.