Y. Zhang
2019
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Abstract
Small molecules are a powerful tool to illuminate biological mechanisms and assist in the identification and validation of therapeutic targets. In this talk, I will describe i) the discovery of a covalent small molecule inhibitor targeting an engineered oncogenic KRAS allele using fragment-based small molecule design approach; ii) 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). Specifically, a biodegradable nanoparticle carrier was employed to aid in IKE delivery in vivo. Besides, a mass spectrometry-based untargeted lipidomics study was carried to illuminate lipid metabolism features in system xc – inhibition and ferroptotic cell death. Collectively, this work illustrates how chemistry and chemical biology approaches can supplement existing efforts towards the design and discovery of small molecule inhibitors for challenging targets, as well as aid in the study of therapeutic mechanisms. Thesis Defense in Chemistry