M.S. Pharmaceutical Sciences
Chemistry and Biochemistry
College of Science & Mathematics
Manoj K. Pandey, Ph.D.
Committee Member 1
Subash Jonnalagadda, Ph.D.
Committee Member 2
Kandalam Ramanujachary, Ph.D.
Myeloid cell leukemia 1 (Mcl-1), Mcl-1 inhibiting agent KS18
Pharmacy and Pharmaceutical Sciences
Multiple Myeloma (MM) is a deadly blood malignancy, characterized by the uncontrolled proliferation of aberrantly differentiated plasma cells. MM is challenging to diagnose and treat, accounting for approximately 12% of hematologic malignancies. The overexpression of anti-apoptotic group of Bcl-2 family proteins, particularly Myeloid cell leukemia 1 (Mcl-1), play a critical role in the pathogenesis of MM. The overexpression of Mcl-1 is associated with drug resistance and overall poor prognosis. Thus, inhibition of the Mcl-1 protein is an attractive therapeutic strategy against myeloma cells. Over the last decade, the development of selective Mcl-1 inhibitors has seen remarkable advancement. In this project, we investigated the effect of the novel Mcl-1 inhibiting agent KS18 on MM cells. We demonstrated the molecules in vitro efficacy as well superior potency towards MM. However, Mcl-1 inhibition by KS18 was associated with a significant reduction of MM cell viability. Moreover, we observed that KS18 was able to induce apoptosis in MM cells in a caspase-dependent manner. Our results propose that targeting Mcl-1 by KS18 may represent a new viable strategy for MM treatment. Furthermore, the present study uncovers the mechanism of action of KS18 and provides the foundation for in vivo assessment of this novel molecule.
Al Odat, Omar S., "SELECTIVE SMALL MOLECULE TARGETING OF MCL-1 IN MULTIPLE MYELOMA" (2022). Theses and Dissertations. 2965.