Date Approved
6-20-2024
Embargo Period
6-24-2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (Ph.D.)
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.
Committee Member 3
Lark Perez, Ph.D.
Committee Member 4
Amos Mugweru, Ph.D.
Keywords
Bcl-2; Bortezomib; Drug resistance; Mcl-1; Multiple myeloma (MM); Venetoclax
Subject(s)
Multiple myeloma; Drug development
Disciplines
Chemistry | Medicinal and Pharmaceutical Chemistry
Abstract
Despite a record number of clinical studies investigating various anti-myeloma treatments, the 5-year survival rate for multiple myeloma (MM) patients in the US is only 55%, and nearly all patients relapse. Poor patient outcomes demonstrate that myeloma cells are "born to survive” which means they can adapt and evolve following treatment. Thus, new therapeutic approaches to combat survival mechanisms and target treatment resistance are required. Importantly, Mcl-1, anti-apoptotic protein, is required for the development of MM and treatment resistance. This study looks at the possibility of KS18, a selective Mcl-1 inhibitor, to treat MM and overcome resistance. Our investigation demonstrates that KS18 effectively induces cell death in MM by dual regulatory mechanisms targeting Mcl-1 protein at both transcriptional and post-translational levels. KS18 triggered caspase-dependent apoptosis in MM patient samples and bortezomib-resistant cells, synergizing with venetoclax to boost apoptosis. Furthermore, the study shows the tremendous impact of KS18 in inhibiting colony formation in bortezomib-resistant cells and demonstrates tumor shrinkage in KS18-treated NSG mice without notable toxicity signs, indicating its powerful anti-neoplastic and anti-resistance characteristics. This study strongly implies that KS18 may treat MM and provide new hope to patients who are experiencing recurrence or resistance.
Recommended Citation
Al-Odat, Omar Sami Faleh, "POTENT AND SELECTIVE SMALL MOLECULE MCL-1 INHIBITOR DEMONSTRATES ANTI-MYELOMA ACTIVITY AND OVERCOMES CHEMOTHERAPY RESISTANCE" (2024). Theses and Dissertations. 3254.
https://rdw.rowan.edu/etd/3254
