Date Approved

1-24-2022

Embargo Period

1-25-2022

Document Type

Thesis

Degree Name

M.S. Pharmaceutical Sciences

Department

Chemistry and Biochemistry

College

College of Science & Mathematics

Advisor

Manoj K. Pandey, Ph.D.

Committee Member 1

Subash Jonnalagadda, Ph.D.

Committee Member 2

Kandalam Ramanujachary, Ph.D.

Keywords

Myeloid cell leukemia 1 (Mcl-1), Mcl-1 inhibiting agent KS18

Subject(s)

Multiple Myeloma--Treatment

Disciplines

Pharmacy and Pharmaceutical Sciences

Abstract

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.

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