Drug discovery efforts targeting mutant p53 for the treatment of glioblastoma.
Date of Award
College of Liberal Arts
Bachelor in Arts
Targeted approaches to treating cancers including glioblastoma multiforme (GBM) are limited and partially effective, at best. By attacking specific oncogenic drivers for a tumor, an on-target and effective drug might be possible. The transcription factor p53 is a cell control tumor suppressor protein responsible for maintaining the integrity of a cell's genome and eliminating cells with DNA mutations. Mutant p53 is found, and believed to be causative, in 50% of all human cancers. The oncogenic driver for a high percentage of GBM is thought to be mutant p53. In this thesis, a drug discovery effort that targets mutant p53 in GBM cells is described. The goal is to identify compounds that reactivate mutant p53 and allow normal biological function of p53 in the GBM cells. The process of identification of lead structures and efforts in developing new analogues that optimize potency, selectivity, metabolic stability and other drug-like properties, including the ability of the compounds to cross the blood brain barrier, BBB, are explained. Crossing the BBB is a critical step for drugs used in central nervous system (CNS) diseases. Here, seven synthesized compounds in two classes, quinoline and benzimidazoles, are discussed. Six of these compounds reactivate mutant p53 in the GBM cells and allow for production of proteins downstream of p53. Of these six active compounds, three cross the blood brain barrier. A structure activity relationship, SAR, regarding in-cell potency, selectivity, metabolic stability and the ability to cross the BBB is then developed. This SAR and drug discovery effort can be further expanded to develop compounds with an optimized biological profile that would lead to potential drug candidates for the treatment of glioblastoma multiforme.
Barsoom, Randa R., "Drug discovery efforts targeting mutant p53 for the treatment of glioblastoma." (2014). Drew Theses and Dissertations. 4.