Type
Text
Type
Dissertation
Advisor
Miller, W. Todd | Seeliger, Markus A | Garcia-Diaz, Miguel | Shan, Yibing.
Date
2014-12-01
Keywords
Pharmaceutical sciences
Department
Department of Molecular and Cellular Pharmacology.
Language
en_US
Source
This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree.
Identifier
http://hdl.handle.net/11401/76518
Publisher
The Graduate School, Stony Brook University: Stony Brook, NY.
Format
application/pdf
Abstract
Dysregulated kinase activity is implicated in a wide variety of diseases because of the central role of kinases in many cell signaling pathways. Currently all small molecule kinase inhibitors used clinically target the ATP-binding pocket, which is highly conserved among all kinases due to their common use of ATP. This high degree of conservation makes the pharmacological targeting of individual kinases difficult. However, it has been achieved with several drugs, the most famous of these being the Abl kinase inhibitor imatinib (Gleevec, Novartis). While a number of broad-spectrum kinase inhibitors are in clinical use, specific kinase inhibition is favorable to avoid potential undesirable side effects. Typically, the focus is on the specificity of the kinase inhibitor and not on the ability of a kinase to bind multiple inhibitors promiscuously. However, it is equally important to understand the specificity of a kinase for inhibitors since some promiscuous kinases bind a large number of kinase inhibitors, in some cases with higher affinity than their intended targets. It is unknown how these promiscuous kinases are able to accommodate such a wide variety of inhibitors. To develop more specific small molecule kinase inhibitors, both aspects of the kinase-inhibitor specificity relationship need to be explored. To address how inhibitors can achieve greater specificity, I characterized and determined the molecular mechanism of unusually specific macrocyclic peptide inhibitors of Src. These compounds are the first to distinguish Src kinase from other Src family kinases. To address kinase promiscuity, I examined how the receptor tyrosine kinase DDR1 binds to different classes of inhibitors. I determined that the promiscuity of DDR1 is due to a large hydrophobic pocket in the active site of the kinase that is formed when the kinase is in an inactive conformation. This inactive conformation is stabilized by unique interactions within the kinase domain. Consequently, disruption of these interactions by mutation increases the activity of the DDR1. These studies demonstrate that specific kinase inhibition can be achieved by targeting unique binding pockets in the active site of a kinase, decreasing the chance that new small molecule inhibitors will bind to promiscuous kinases like DDR1. | 153 pages
Recommended Citation
Georghiou, George, "Molecular mechanisms for specific kinase inhibitors and kinase promiscuity towards inhibitors" (2014). Stony Brook Theses and Dissertations Collection, 2006-2020 (closed to submissions). 2425.
https://commons.library.stonybrook.edu/stony-brook-theses-and-dissertations-collection/2425