Date of Award
Doctor of Philosophy (PhD)
Microbiology, Molecular Biology and Biochemistry
Protein-tyrosine kinases (PTKs) play essential roles in the cell signaling pathways of eukaryotes. However, since their discovery, PTKs have also been linked to cancer and it is now known that many of these enzymes actively promote oncogenic cell signal transduction in unregulated forms. Therefore, there has been a concerted effort on the part of researchers to identify the PTKs that potentiate such pathways, characterize their regulatory properties, and develop strategies to selectively disrupt these key elements of oncogenic signaling. Following this strategy, work described in this dissertation first focuses on the characterization of a relatively unstudied PTK, known as SRMS, which may be linked to cancer. To accomplish this, a novel strategy was developed to purify active SRMS, which can also be used to purify other PTKs for in vitro biochemical studies. Additionally, the purified SRMS was shown to activate upon autophosphorylation of the activation loop tyrosine, representing the first known regulatory mechanism of SRMS. The second focus of this dissertation was to develop a novel strategy for the design of selective PTK inhibitors. Using dasatinib, an established small-molecule inhibitor, a series of carboxyester-linked derivatives were synthesized and evaluated against a panel of PTKs. The biochemical data obtained presents a library of compounds with modified specificity toward individual PTKs. Thus, this strategy represents a break-through in the development of new, more selective PTK inhibitors for use as medicinal drug lead compounds.
Brown, Alexander IV, "Novel Strategies for the Purification and Inhibition of Protein-Tyrosine Kinases" (2014). Open Access Dissertations. Paper 216.