Dr. William Windsor
- Ph.D. (Biophysical Chemistry) - 1984, University of Connecticut
- B.S. (Physics) - 1977, Northeastern University
BIOPHYSICAL CHEMISTRY LABORATORY FOR DRUG DISCOVERY
RESEARCH: Drug Discovery for Oncology Targets
LABORATORY FOCUS: Preclincal Drug Discovery using Biochemical and Biophysical Methods to Evaluate Drug-Protein and Protein-Protein Intertactions.
RESEARCH APPLICATIONS: Biotechnology & Pharmaceutical Research
RESEARCH TRAINING: Biochemists, Chemical Biologists, Biological Scientists
Protein – Drug Binding / Mechanism of Action
- Elucidate binding affinity of inhibitors/ligands
- Determine mechanism of action (MOA) for lead small molecule inhibitors/ligands
- Competitive, non-competitive, uncompetitive; reversible/irreversible
- Kinetics of binding (kon, koff)
- Establish consistent structure activity relationship (SAR) per class of compounds
- Characterize thermodynamics and stoichiometry of binding
- Measure the affinity and kinetics of ligand / drug binding to proteins / DNA by Surface Plasmon Resonance (SensiQ Pioneer)
- Evaluate protein fold by measuring secondary structure content using circular dichroism
- wild type vs. mutant protein constructs
- Determine protein structural stability and ligand binding affinity using thermal protein melting methods (Thermofluor or CD)
- Applications: proteases, polymerases, kinases, cytokines, transferases, scaffolding proteins, etc.
Characterization of Base Pairing for DNA/RNA and Lipid Interactions
Biophysical Chemical Instruments
- BioForte Pioneer FE Surface Plasmon Resonance
- Jasco J810 CD Spectropolarimeter
- QuantStudio 5 qPCR / Thermal Shift Instrument
- Envision Plate Reader
- Spectromax Gemini & 384 Plus plate readers.
Adjunct Professor and Visiting Scholar in the Department of Chemistry and Chemical Biology. Directs the Biochemistry and Biophysical Chemistry Lab for Drug Discovery.
Most recently the Director of the Biochemistry & Biophysics Department at the Merck Research Laboratory and Director of Kinase Research at Schering-Plough Research Institute (SPRI). He has over 34 years’ experience in preclinical drug discovery and is an expert in biochemical and biophysical analysis of protein-ligand / protein-protein interactions, enzymology and structure-based drug design to elucidate the mechanism of action of small molecule inhibitors. Dr. Windsor has extensive experience in methods of calorimetry (ITC, DSC), circular dichroism, absorbance and fluorescence spectroscopy and protein purification. Dr. Windsor is recognized as one of the first scientists at SPRI to develop an expertise in protein kinase biochemistry and due to his experience and leadership skills became the Chairman of a 100 member cross-functional Protein Kinase Working Group which developed state of the art methods to discover and develop clinical kinase inhibitor drugs. His preclinical research focused on oncology and immunology/inflammation diseases. Noted outstanding accomplishments include the development of seven clinical drugs including: Sarasar (FPT inhibitor for Progeria and Oncology), HCV protease inhibitor Boceprevir, kinase inhibitors Dinaciclib (CDK2) and ERK inhibitor SCH 900353. Dr. Windsor was awarded the Schering-Plough Presidential Research Award for the discovery of Dinaciclib and for the X-ray Structure of FPT and is an author and co-inventor for over 50 publications and patents.
Zhang R, Windsor W.T. (2013) "In vitro kinetic profiling of hepatitis C virus NS3 protease inhibitors by progress curve analysis." Methods Mol Biol. 1030 59-79.
Morris EJ, Jha S, Restaino CR, Dayananth P, Zhu H, Cooper A, Carr D, Deng Y, Jin W, Black S, Long B, Liu J, Dinunzio E, Windsor W, .... Samatar A.A. (2013) "Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors." Cancer Discov. 3 742-50.
Parry D., Guzi T., Shanahan F., Davis N., Prabhavalkar D., Wiswell D., Seghezzi W., Paruch K., Dwyer M., Doll R., Nomeir A., Windsor W., Fischmann T., Wang Y., Oft M., Chen T., Kirschmeier P., Lees E. (2010) “Dinaciclib (SCH 727965), a Novel and Potent Cyclin-Dependent Kinase Inhibitor” Mol Cancer Ther 9 2344-53.
Lu Z., Cox-Hipkin MA., Windsor W., Boyapati A. (2010) “3-Phosphoinositide-dependent Protein Kinase-1 Regulates Proliferation and Survival of Cancer Cells with an Activated Mitogen-Activated Protein Kinase Pathway” Mol Cancer Res. 8 421-32.
Fischmann T.O., Hruza A., Duca J.S., Ramanathan L., Mayhood T., Windsor W., Le H.V., Guzi T.J., Dwyer M.P., Paruch K., Doll R.J., Lees E., Parry D., Seghezzi W., Madison V. (2008) “Structure-Guided Discovery of Cyclin-Dependent Kinase Inhibitors.” Biopolymers 89 372-379.
Annis D.A., Shipps G.W. Jr, Deng Y., Popovici-Müller J., Siddiqui M.A., Curran P.J., Gowen M., Windsor W. (2007) “Method for Quantitative Protein-Ligand Affinity Measurements in Compound Mixtures.” Anal. Chem. 2007 79 4538-4542.
Smith C.K., Windsor W. (2007) “Thermodynamics of Nucleotide and Non-ATP Competitive Inhibitor Binding to MEK1 by Circular Dichroism and Isothermal Titration Calorimetry.” Biochemistry 46 1358-1367.
Smith C.K., Carr D., Mayhood T.W., Jin W., Gray K., Windsor W. 2007 “Expression and Purification of Phosphorylated and Non-phosphorylated Human MEK1.” Protein Expr. Purif. (2007) 52 446-56.
Mayhood T.W. and Windsor W. (2005) “Ligand Binding Affinity Determined by Temperature-Dependent Circular Dichroism: Cyclin-Dependent Kinase 2 Inhibitors.” Anal. Biochem. 345 187-97.
Nallan, L., Bauer, K., Bendale, P., Rivas, K., Yokoyama. K., Horney C.P., Pendyala, P., Floyd, D., Lombardo, L., Williams, D., Hamilton, A., Sebti, S. Windsor, W., Weber P. C ., W., Buckner, F., Chakrabarty, Gelb, M., Van Voorhis, W. (2005) “Protein Farnesyltransferase Inhibitors Exhibit Potent Anti-Malarial Activity“, J. Med. Chem. 48 3704-13.
Zhang, R., Mayhood, T., Lipari, P., Wang, Y., Durkin, J., Syto, R., Gesell, J., McNemar, C., Windsor, W. (2004) “Fluorescence Polarization Assay and Inhibitor Design for MDM2/p53 Interaction” Anal Biochem. 33 138-46.
Hosted, Thomas J.; Simon, Jason S.; De Lorenzo, Marc M.; Carr, Donna Marie; Windsor, William T.; Samatar, Ahmed A. (2009) “BRAF Biomarkers” WO2009073513 A1
Taremi, Shahriar Shane; Xie, Gaolian ; Hesson, Thomas ; Duca, Jose S. ; Strickland, Corey ; Windsor, William T. ; Madison, Vincent S. ; Zhang, Rumin ; Reichert, Paul ; Wang, Yaolin; (2009) “Soluble, stable form of HDM2, crystalline forms thereof and methods of use thereof” US7632920 B2
Deng, Yongqi; Curran, Patrick J.; Shipps, Jr., Gerald W.; Zhao, Lianyun; Siddiqui, M. Arshad; Popovici-Muller, Janeta ; Duca, Jose S. ; Hruza, Alan W. ; Fischmann, Thierry O. ; Madison, Vincent S.; Zhang, Rumin; McNemar, Charles W.; Mayhood, Todd W.; Windsor, William T.; Lees, Emma M.; Parry, David A. (2009) “High affinity quinoline-based kinase ligands” US7511063 B2
Deng, Yongqi; Zhao, Lianyun; Shipps, Jr., Gerald W.; Curran, Patrick J.; Siddiqui, M. Arshad; Zhang, Rumin; McNemar, Charles W.; Mayhood, Todd W.; Windsor, William T.; Lees, Emma M.; Parry, David A. (2008) “High affinity thiophene-based and furan-based kinase ligands” US7446195 B2
Zhang, Rumin; Zou, Jun; Zhu, Feng X.; Durkin, James P.; Windsor, William T.; Umland, Shelby P. (2006) “Peptide substrates of a proteolytic ADAM33 polypeptide and assays using the same” US7067273 B2
Windsor, W., Weber, P., Strickland, C., Gelb, M. (2003) “Treatment of Malaria with Farnesyl Protein Transferase Inhibitors” Patent# US 6,645,966
Strickland, Corey, Wu, Zhen, Windsor, William T., Weber, Patricia (2003) “Crystallizable Farnesyl Protein Transferase Compositions, Crystals thereby Obtained, and Methods for Use.” Patent # US 6,539,309 B1
- BME 690 Cellular Signal Transduction
- CH 582 Biophysical Chemistry
- BIO 682 Biochemical Laboratory Techniques
- BIO 690 Celluar Signal Transduction