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U.S. National Institutes of Health
Last Updated: 10/28/10

The University of Pittsburgh Chemical Diversity Center

Chemistry-Driven Drug Discoveries

The University of Pittsburgh Chemical Diversity Center (UP-CDC) takes advantage of the capabilities and expertise that reside in the Informatics & Computational Chemistry, Medicinal Chemistry and Synthetic Chemistry Cores of the University of Pittsburgh Drug Discovery Institute (UPDDI) and the University of Pittsburgh Center for Chemical Methodologies and Library Development (UPCMLD). Specifically, we have capabilities, experience and expertise in ChemInformatics, synthetic methodology, computational chemistry, laboratory automation, library synthesis, library QC, medicinal chemistry, natural products chemistry, organic synthesis on milligram to multi-gram scale, pharmaceutical properties (ADME/Tox) analysis and optimization, structure-based drug design, and drug discovery and development. We have in place protocols for hit/scaffold assessment, triage, and optimization; library purification by mass-guided LC/ MS and QC analysis, including heavy metal content by ICP-OES, lead optimization for potency, selectivity and pharmaceutical properties; and identification and development of clinical candidates. We have a strong tradition of collaborative research with internal as well as external scientists that have resulted in significant scientific contributions in the areas of chemical biology and drug discovery and to the advancement of nearly 40 small molecules into clinical trials, as well as to the discovery and development of two marketed cancer drugs.

Three cores comprise the UP-CDC. The Medicinal Chemistry Core is led by the PI, Professor Donna Huryn, and contributes to hit validation and triage; hit-to-lead activities; the design and synthesis for SAR and Structure-Property Relationships (SPR) development (e.g., lead optimization); design and synthesis of analogs to address ADME/Tox deficiencies; and the preparation of labeled versions of lead compounds. The Synthetic Chemistry Core has responsibility for synthesis route selection and methodology development; library synthesis; natural product chemistry; analytical chemistry support; compound storage, handling and shipping; and scale-up synthesis. Professor Peter Wipf leads the Synthetic Chemistry Core. The Informatics & Computational Chemistry Core, led by Dr. Gabriela Mustata, has state-of-the-art capabilities in cheminformatics, virtual screening, pharmacophore modeling, quantitative SAR (QSAR); quantitative SPR (QSPR); in silico ADME and Toxicology model development and prediction; in silico library enumeration and diversity analysis, library design, docking, and scoring; and structure-based drug design. Even though we have assigned specific activities to each core, all three cores work collaboratively.

The University of Pittsburg Chemical Diversity Center

Cores of the UP-CDC: Key Affiliations

University of Pittsburgh Center for Chemical Methodology and Library Development (UPCMLD)

The membership of the UPDDI Chemistry Core overlaps and synergizes with that of the UPCMLD. The UPCMLD was established in 2002 as one of the original two centers funded by NIH, and was reselected in the fall of 2008 as one of the five new centers funded through the second grant period (2008-2013). It is a leader in the development of novel chemical methodologies and their application to library synthesis, as well as in synthesis automation and library purification; since 2002, UPCMLD scientists have published >150 papers on these topics. To date, the UPCMLD Diversity-Oriented Synthesis (DOS) Core has completed the production of 23 novel libraries, comprising >3,000 individual compounds. While the primary focus of the UPCMLD is on the development of new synthetic methodologies, we have always pursued an active and highly successful biology outreach program that has led to the identification of novel biological probes from UPCMLD libraries. For example, the UPCMLD developed the first selective probe of the heat shock protein, HSP70. Subsequent optimization libraries based on the structure of this probe have generated additional novel agents that are currently being evaluated in models of malaria, cancer, and T. brucei infection. In addition, a probe of MKP-1 was identified from a CMLD library compound.

University of Pittsburgh Drug Discovery Institute (UPDDI)

UPDDI is committed to identifying small molecules that can be used as chemical probes for biological activities and as leads for new therapies for human diseases. The UPDDI uses the latest advances in scientific understanding of cell signaling processes and disease states, laboratory automation and compound storage/retrieval, data management, combinatorial chemistry and diversity-oriented synthesis as a foundation for its drug discovery efforts. The Institute is a model of collaboration, comprising faculty members from three schools at the University of Pittsburgh, housed in a recently built research facility. It is in the unique position to balance academic research flexibility with industrial compound screening and development efficiency.

University of Pittsburgh Cancer Institute Molecular Therapeutics and Drug Discovery/ Development Program

The UPDDI is closely linked with the University of Pittsburgh Cancer Institute (UPCI), which is an NCI-designated Comprehensive Cancer Center. The UPCI has more than 625 research faculty members specializing in disciplines ranging from cancer prevention and early detection to novel therapeutic discovery, survivorship, and end of life care. The Molecular Therapeutics and Drug Discovery/Development Program (MT/DD) based in the UPCI promotes interactions of basic, preclinical, and clinical researchers to develop innovative approaches to drug treatment. The program comprises a multidisciplinary group of scientists committed to making basic laboratory observations about therapeutic targets and potential strategies, exploring their feasibility in preclinical models, and translating the most promising approaches and molecules into the clinical setting. The MT/DD Program has focused on establishing a strong basic science foundation for the development of small molecule anti-cancer agents and novel therapeutic approaches to malignancy.

UP-CDC Expertise in Target Class, Compound Class/Scaffolds, Chemistries & Technologies

Target Classes ABC Transporters, Anti-metabolites, Cell Cycle Inhibitors, Cell Adhesion Molecules, GPCR’s, Heat Shock Proteins, Hormone Receptors, Ion Channels, Kinases, Microtubule Stabilizing Agents, & Destabilizing Agents, Mitochondrial Targeting, Nucleic Acid Binding Proteins, Oncogenes, Phosphatases, Polymerases, Proteases, Protein-protein Interactions Reverse Transcriptase, ROS–Scavenging, Steroid Receptors, Transporters, Whole Organism Assays, Zebrafish Assays
Compound Classes/ Scaffolds Amino Acids, Amino Acid Isosteres, Azepines, Azoles, Carbohydrates, Ceramides, Imidazoles, Indoles, Marine Natural Products, Peptides, Natural Products, Nucleic Acids, Nucleosides, Oxazoles, Peptide Isosteres, Peptidomimetics, Piperidines, Pyrrolidines, Steroids, Terpenes, Thiazoles, Thiolactones, Thiophenes
Chemistries Cascade Radical Reactions, Heterocyclic Chemistry, Multi-component Reactions, Natural Product Total Synthesis & Semi-synthesis, Organometallic Reactions, Peptide Synthesis, Pericyclic Reactions, Transition Metal Catalyzed Reactions
Technologies Automation, Flow Reactor Chemistry, Fluorous-phase Synthesis, ICP-ORS for Trace and Heavy Metal Analysis, Library Synthesis, Mass-directed Preparative HPLC, Microwave Chemistry, Solid-phase Organic Synthesis, Solid-phase Peptide Synthesis, Photoaffinity Labeling, Radiolabelling, Analytical and Preparative Supercritical Fluid Chromatography, Trace Metal Analysis
Computational Chemistry Capabilities Ligand-based Design (GALAHAD, Tuplets, Topomer CoMFA, QSAR, VolSurf and Almond/Tripos, QuaSAR, Pharmacophore Discovery/MOE); Structure-based Design (SurflexDock and CScore/Tripos, LigX/MOE); Cheminformatics (Topomer Search, UNITY Base, Unity 3D, CONCORD, StereoPlex/Tripos); Virtual Library Design and Analysis (CombiLibMaker/Legion, Selector, Diverse Solutions/ Tripos, MOE); Protein-protein Interactions (ClusPro, SmoothDock, FastContact); Homology Modeling (Modeller and Consensus); Diversity Analysis (Principle Component Analysis, Chem GPS); Property Prediction (QikProp, ADMET Predictor)
Other Capabilities Microsomal Stability, Metabolite Identification, Mechanism of Action Studies, Pro-drugs and Drug Targeting