Dr. Wang’s lab conducts basic and translational research on oncogenic protein kinases in the area of cancer biology. The main focus is on diacylglycerol (DAG)-targeted protein kinases, particularly protein kinase D (PKD) and protein kinase C (PKC) family kinases. DAG is a key second messenger generated in cells in response to the activation of receptor tyrosine kinases and G protein-coupled receptors. It acts to disseminate vital signals from the cell surface to the cell interior. PKD and PKC are primary targets of DAG that regulate many fundamental cellular processes such as cell growth, survival, apoptosis, motility, and protein trafficking. In particular, PKD is at the center of the DAG signaling network, integrating signals from both DAG and PKC. In recent years, PKD has emerged as a promising therapeutic target for several diseases including cancer and heart disease. Deregulated PKD expression and activity have been demonstrated in a variety of pathological conditions, suggesting an active contribution to disease initiation and progression.
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Structure and regulation of PKD
We seek to understand both the basic structure of PKD and how different structural domains in PKD interact to regulate its activity and function. We are particularly interested in the C1 domain, the high affinity DAG binding domain shared among all DAG receptors. Our previous studies identified PKD as a high affinity receptor for DAG and defined the structure-activity requirements for the binding of the PKD C1 domain to DAG and phorbol esters. This work has provided the basis for ligand-specific regulation of PKD isoforms. Our long-term goal is to investigate the intra- and intermolecular regulatory mechanisms controlling PKD activity and assess their impact on the function of PKD in intact cells. Ultimately, we seek to solve the 3D structure of this protein.
<img style="HEIGHT: 266px; WIDTH: 240px" alt="" src="http://www.pharmacology.us/ContentPics/634461477034680608Picture1.jpg" align="left" hspace="10" vspace="10">PKD as a novel therapeutic target in cancer
Growing evidence has implicated PKD in the pathogenesis of cancer. Using prostate cancer as a model, we will determine the functional relevance and signaling mechanisms of PKD in cancer. We will elucidate the signaling pathways both upstream and downstream of PKD and identify novel PKD substrates relevant to cancer promotion. In previous studies, we have identified PKD3 as a downstream target of the oncogenic kinase PKCe. We found that PKD3 acts through a hyperactive PKCe/PKD3 pathway to modulate the activity of ERK1/2 and Akt signaling, contributing to the growth and survival of prostate cancer cells. Another active area of research in our lab is to determine the in vivo relevance of PKD signaling to cancer. We use a variety of animal models including mouse xenograft models and transgenic/knock-out mice to determine the role of PKD in prostate cancer initiation, progression, and metastasis. In addition, we also study the cross-regulation between PKD and androgen receptor signaling and its implication in prostate cancer. Our studies have now expanded to other types of solid tumors such as head and neck cancer and pancreatic cancer. In the long run, we seek to validate PKD as a therapeutic target for cancer therapy.
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Development of small molecule inhibitors of PKD
In this major research endeavor, we seek to develop potent and selective small molecule inhibitors of PKD as pharmacological tools for dissecting PKD-mediated biological processes and as potential drugs for clinical application. This is an important study in the translation of PKD-targeted therapeutics into the clinic. In collaboration with our colleagues at the University of Pittsburgh Drug Discovery Institute and the Department of Chemistry, we have identified the first potent and selective small molecule PKD inhibitor, CID755673, and subsequently developed a class of unique ATP-noncompetitive inhibitors based on this parental compound. These inhibitors are cell-active and exhibit nanomolar potencies, with high specificity for PKD. Future studies are focused on further developing this series of inhibitors for in vivo and clinical application, and continuing our efforts in new drug discovery.
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