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Dr. Altschuler's laboratory studies mechanisms of signal transduction by the second messenger cAMP in cell proliferation. cAMP-dependent protein kinase (PKA) and Exchange protein activated by cAMP (Epac) represent the main effectors of cAMP action. Both pathways converge at the level of the small GTPase Rap1b, via its Epac-mediated activation and PKA-mediated phosphorylation. The role of Rap1 activation (Epac) and phosphorylation (PKA) coordinating the early rate-limiting events in cAMP-dependent cell proliferation are studied using a multidisciplinary approach including molecular and cellular biology techniques in vitro, as well as in vivo validation using transgenic/knock in technologies in endocrine tumor models.
1) The discovery of new small organic molecules that inhibit or activate specific biological pathways is a major research topic in the lab. Our discovered microRNA inhibitors have therapeutic implications in cancer and viral infections. 2) We are genetically re-wiring the circuitry of bacterial and mammalian cells in order to give new functions to proteins and organisms. Our approach is based on the expansion of the genetic code with synthetic, unnatural amino acids. 3) Light is a unique control element that enables the regulation of biological processes with high spatial and temporal resolution. We are engineering light-responsive nucleic acids and proteins, and are applying them in cellular optobiological studies.
Our research is directed toward developing fundamentally new transformations and highlighting their utility for complex molecule synthesis.
Dr. Johnston has over two decades of drug discovery experience in the pharmaceutical, biotechnology and academic sectors. Since joining the University of Pittsburgh Department of Pharmacology & Chemical Biology in 2005 to help design and build the infrastructure for a high-throughput drug discovery screening center at the Drug Discovery Institute, Dr. Johnston has led 21 screening campaigns, and reconfigured the NCI 60 cell line assays for cancer drug combination screening. In 2011, Dr. Johnston joined the Department of Pharmaceutical Sciences in the School of Pharmacy to establish chemical biology laboratories, where he has continued to conduct his research in high-throughput and high-content screening (HTS/HCS) assay development and implementation, and to establish drug discovery collaborations throughout the scientific community. His research has focused on pursuing chemical biology approaches to identify small molecules with the potential to be developed into new therapies for prostate cancer, melanoma and head and neck cancer.
We are currently studying FR901464, a natural product that regulates cancer-related genes by novel mechanisms. This compound inhibits cancer proliferation at concentrations as low as 1 nM. To study FR901464, we completed a chemical total synthesis of this natural product. Combination of this powerful, stereocontrolled chemical synthesis and cell biology will provide insights into the molecular mechanisms of FR901464. More recently, we have developed an exceptionally active FR901464 analog (meayamycin) that inhibits tumor growth at 10 pM (analogouus to one pack of sugar (5 grams) in 400 Olympic swimming pools).
Glioblastomas are highly invasive primary tumors with poor prognosis despite current therapies. Individual targeted therapies have failed to offer long-term survival benefits, although combinations of rationally selected inhibitors may have significant therapeutic applicability for these tumors. Studies by our group and others have also shown aberrant, constitutive activation of NF-kB and Akt as common features of malignant gliomas, supporting their functional role in contributing to apoptosis resistance and refractory growth despite cytotoxic chemotherapy, irradiation, and molecularly targeted therapies. This activation may in part reflect deletions of NF-kB inhibitor-alpha, a common alteration in malignant gliomas, dysregulated stimulation by cell surface tyrosine kinases, such as EGFR and PDGFR-alpha, which are amplified in molecular subsets of malignant gliomas, and mutations in PTEN and other molecular targets that drive Akt and NF-kB activation. Thus, new therapeutic approaches are urgently needed. We have demonstrated that inhibition of NF-kB, Akt, and Bcl-2 may constitute a promising strategy to enhance the efficacy of conventional therapies, such as irradiation and cytotoxic chemotherapy, and potentiate the activity of agents targeted against growth signaling mediators.
My research interests center on applying a systems biology/pharmacology approach to develop more effective drug discovery strategies that utilize integrated phenotype/function-based analysis (where all targets involved are functioning in a more physiologic relevant environment) and to better understand the molecular mechanisms that cause drugs to succeed or fail in the clinic.
My major research interests center around the discovery of small molecules with phenotypic assays in clinically relevant cellular and whole organism models. It is becoming increasingly clear that better models of the in vivo milieu are needed to improve the discovery of new drug candidates. Zebrafish, C. elegans, and Drosophila in particular provide unique opportunities to discover novel potential therapeutics using functional assays in a living animal as a complement to cellular and tissue model approaches. Together with members in the Departments of Neurology and Developmental Biology, I have established methodology for zebrafish chemical screening, generated automated image analysis tools for quantification of reporter gene expression, and automated neurobehavioral assays in multiwell plate formats. Currently, active zebrafish discovery projects include kidney and heart regeneration, angiogenesis and vascular malformations, early safety assessment, and neurodegenerative diseases. Cancer-related research efforts include the discovery of small molecule modulators of mitogen-activated protein kinase phosphatases (MKPs), PUMA, profilin-1, and estrogen receptor alpha as treatments for metastatic breast and colon cancer.
The Wipf group develops tools of synthetic organic chemistry in the search for innovative new therapies and therapeutics. We identify original synthetic methods, strategies and molecular mechanisms, and we apply them in medicinal chemistry and chemical biology, total synthesis, and natural products chemistry. We select target molecules on the basis of their unique architectures and biological activities, as well as for showcasing our synthetic methods. We employ insights from flow and photochemistry, material science and nanoparticle research to improve synthetic access and modify the properties of our target compounds. Most significantly, we are committed to collaborative drug discovery and development in diverse therapeutic areas, including oncology, neurodegeneration, fibrosis, neuromuscular diseases, inflammation, and immunology.
The research focus of Dr. Xie's laboratory is nuclear receptor-mediated transcriptional regulation of genes that encode drug metabolizing enzymes and drug transporters. In addition to metabolizing drugs, the same enzyme and transporter systems are responsible for the homeostasis of endogenous chemicals. Therefore, besides drug metabolism and disposition, this regulation has broad implications in many human diseases, including liver diseases (fatty liver, liver fibrosis, liver cancer, and autoimmune hepatitis), endocrine disorders, metabolic syndrome, and cancers. Dr. Xie’s research is conducted using a combination of molecular biology and genetically engineered mice that include tissue and cell type-specific transgenic, knockout and humanized mice.