Receptor tyrosine kinases are primary targets for small molecule and monoclonal antibody chemotherapies given their key role in intracellular signaling pathways, regulation of cell growth and cell survival. Immunohistochemical (IHC) analysis of receptor levels is an essential component for cancer classification and attempts to predict the treatment regimens, however, IHC has significant limitations in its predictive value due to the fact that the basic science of receptor signaling has moved well beyond using simple protein levels as an indicator. We now appreciate the importance of kinase activation states that are controlled by multiple factors that have been individually confirmed to be highly relevant for their oncogenic potential. Yet our ability to translate this knowledge into analytical readouts tha are robust and clinically useful is lagging far behind our understanding of signaling events. Our goal is to generate protein kinase specific molecular probes, which will enable detection, quantification and detailed analyses of cancer-relevant signaling pathways alongside dynamic, real time analysis of systemic cellular perturbations. To achieve this goal, we will utilize chemical synthesis to generate candidate probes, characterize their performance as reporters by optical spectroscopy, evaluate their pharmacological properties against relevant cancer signaling pathways and validate their performance against current "gold standard" analytical methods. Successful execution of this research plan will provide a set of probes that provide an optical "fingerprint" with far more informational content and predictive power while being robust in its application for clinical staging, individualized evaluation of drug response, drug development and cancer pathway dissection.
The goal of this research effort is to develop new chemical tools that allow molecular-level investigations of cancer signaling pathways. These molecular probes will 1) enable analysis of drug resistance mechanisms, 2) provide new assays for drug discovery efforts and 3) aid in clinical diagnostics.
|Dhuguru, Jyothi; Liu, Wenjun; Gonzalez, Walter G et al. (2014) Emission tuning of fluorescent kinase inhibitors: conjugation length and substituent effects. J Org Chem 79:4940-7|