Small molecules are a powerful tool to illuminate biological mechanisms and assist in the identification and validation of therapeutic targets. KRAS is the single most frequently mutated oncogene in human cancer, with particularly high mutation frequencies observed in pancreas (95%), colon (45%), and lung (35%) cancer. However, despite three decades of effort, there is no clinical viable KRAS cancer therapy. The first part of this thesis focuses on exploring the potential of directly targeting the KRAS nucleotide binding site. Directly targeting oncogenic KRAS with small molecules in the nucleotide-binding site has had limited success due to the high affinity of KRAS for nucleotide GTP and the high cellular concentration of GTP. The strategy of generating engineered KRAS allele based on shape and covalent complementarity was exploited herein to address this challenge. Using fragment-based small molecule design, a cell-membrane-permeable covalent inhibitor able to irreversibly modify the engineered nucleotide-binding site of KRAS was developed. The second part of this thesis describes the investigation of the therapeutic potential of imidazole ketone erastin (IKE), a small molecule inhibitor of the cystine/glutamate antiporter system xc–, in a subcutaneous xenograft model of Diffuse Large B Cell Lymphoma (DLBCL). A biodegradable polyethylene glycol-poly(lactic-co-glycolic acid) nanoparticle formulation was employed to aid in the delivery of IKE to cancer cells in vivo. This IKE nanoparticle system showed improved tumor accumulation and therapeutic index relative to free IKE, indicating its potential for treating DLBCL. The final part of this thesis describes the study of lipid metabolism features of ferroptotic cell death using quantitative reverse transcription PCR (RT-qPCR) and mass spectrometry-based lipidomic analysis. In summary, this work illustrates how chemistry and chemical biology approaches can supplement existing efforts towards the design and discovery of new drugs for challenging targets, as well as aid in the study of therapeutic mechanisms.
Identifer | oai:union.ndltd.org:columbia.edu/oai:academiccommons.columbia.edu:10.7916/D8WM2XC5 |
Date | January 2019 |
Creators | Zhang, Yan |
Source Sets | Columbia University |
Language | English |
Detected Language | English |
Type | Theses |
Page generated in 0.0026 seconds