Adrian Whitty

Assistant Professor, Department of Chemistry

Biochemistry and Bioorganic Chemistry
- Protein-protein and protein-ligand interactions
- Molecular mechanisms of growth factor receptor
activation and signaling
- Inhibitors and activators of protein-protein
interactions

Office: SCI 359
Phone: 617-353-2488
Fax: 617-353-6466
E-mail: whitty@bu.edu

Office hours: By appointment

• - B.Sc. (Hon) in Chemistry, King's College, University of London, 1985
• - Ph.D. in Organic Chemistry, University of Illinois at Chicago, 1991
• - Postdoctoral Research Fellow, Brandeis University, Graduate Department of Biochemistry, 1990-93

• Director, Physical Biochemistry (2/07-4/08), Associate Director & Head, Physical Biochemistry (1/03-1/07), Biogen Idec Inc., Cambridge, MA
• Senior Scientist (1999-2002), Drug Discovery Department, Biogen Inc. Cambridge, MA

• Director, Biogen Idec Postdoctoral Program, 2005-4/08

  Cited in Science as a top postdoc mentor (“Success Factors for Postdocs”, Sept 17, 2004)

• Membership Committee, The Protein Society, 2008-present

  Member, Governing Council, American Society of Biochemistry and Molecular Biology (ASBMB), 2007-present

  Founding Member, Council for Systems Biology in Boston (CSB2), 2007-present

  Scientific Advisory Board, CHI Conference on Fragment-Based Drug Discovery, May 2007

  Member, National Science Foundation review panel for grant proposals on Cellular and Biomolecular Engineering, January 2007

  Chair, ‘Membranes’ session, Nature Chemical Biology Symposium on “The Chemical Biology of the Cell”, November 2006

  Member, professional advising committee, MIT Undergraduate Biochemistry Association

  Organizing Committee, GTCBio conference “Cytokines and Inflammation”, January 2000.

  Advisory Board Member, Institute for Chemical Biology and Drug Discovery, SUNY Stony Brook (2004-present)

  Co-Chair, 2002 Gordon Research Conference on Bioorganic Chemistry

• CH 203 - Organic Chemistry

Research in my laboratory is directed towards two main problems: (1) Mechanisms of receptor activation and signaling in growth factor receptor systems (for a recent example, see Schlee et al., Nat. Chem. Biol. 2006), and (2) The discovery and characterization of small molecule (i.e. synthetic organic) inhibitors of protein-protein interactions (see Whitty and
Kumaravel, Nat. Chem. Biol. 2006; He et al., Science 2005). This latter work will be conducted in collaboration with the CMLD-BU. These two main areas of research share the broad themes of protein-protein and protein-ligand recognition, and how the binding energy that is generated by such intermolecular interaction can be exploited to achieve biological function or inhibition. The lessons learned are therefore broadly applicable to a wide range of biological systems in which proteins interact with each other or with small organic ligands.

Students and other trainees in my group will have the opportunity to learn a broad range of experimental techniques, such as the development and implementation of biochemical and cell-based assays, biophysical methods (e.g. surface plasmon resonance [Biacore], fluorescence polarization, etc.), mammalian cell culture, specialized techniques for cell analysis (e.g. flow cytometry), and quantitative data analysis, curve fitting and reaction pathway modeling. Most importantly, students will be trained in rigorous, hypothesis-driven experimental design and interpretation. The training provided is intended to prepare students for future careers in either academia or industry.

Under Construction

• Peer-Reviewed Publications

• "Quantification and Modeling of Tripartite CD2, CD58-Fc Chimera (Alefacept) and CD16 Mediated Cell Adhesion " M.L. Dustin, T. Starr, D Coombs, G. Majeau, W. Meier, P. Hochman, A. Douglass, R. Vale, B. Goldstein and A. Whitty, J. Biol. Chem., 242, 34748-34757 (2007).

  “Quantitative Analysis of the Activation Mechanism of the Multi-Component Growth Factor Receptor Ret”, S.Schlee, P. Carmillo and A. Whitty, Nature Chemical Biology, 2, 636-644 (2006). (Accompanying News & Views article: Nature Chemical Biology, 2, 569-570 (2006). Cited as a ‘Research Highlight’, Nature, 443, 727 (2006).)

• “Between a Rock and a Hard Place?”, A. Whitty and G. Kumaravel (Invited commentary on developing small molecule inhibitors of protein-protein interactions), Nature Chemical Biology, 2, 112-118 (2006).

• “The Formation of Virus-Like Clusters is an Intrinsic Property of the TNF Family Member BAFF/BlyS”, T.G. Cachero, F. Qian, I.M. Schwartz, E.S. Day, D. Krushinskie, J. Eldredge, A. Tardivel, C. Bossen, L. Silvian, A. Lugovskoy, G.K. Farrington, K. Strauch, P. Schneider, and A. Whitty. Biochemistry, 45, 2006-2013 (2006)

  "N-erminally PEGylated Human Interferon-b-1a with Improved Pharmacokinetic Properties and In Vivo Efficacy in a Melanoma Angiogenesis Model", D.P. Baker, E.Y. Lin, K.C. Lin, M. Pellegrini, R.C. Petter, L.L. Chen, R.M. Arduini, M Brickelmaier, D Wen, D.M. Hess, L. Chen, D. Grant, A. Whitty, A. Gill, D.J. Lindner, and R.B. Pepinsky. Bioconjugate Chemistry, 17, 179-188 (2006).

  “Small-Molecule Inhibition of TNF-alpha”, M.M. He, A. Stroustrup Smith, J.D. Oslob, W.M. Flanagan, A.C. Braisted, A. Whitty, M.T. Cancilla, J. Wang, A.A. Lugovskoy, J.C. Yoburn, A.D. Fung, G.K. Farrington, J. Eldredge, E.S. Day, L.A. Cruz, T.G. Cachero, S.Miller, J.E. Friedman, I.C. Choong, B.C. Cunningham. Science, 310, 1022-1025 (2005). (‘Editor’s Choice’, Sci. STKE 2005, tw409 (2005))

• "Glial Cell Line-Derived Neurotrophic Factor (GDNF) Receptor Alpha-1 (GFRa1) is Highly Selective for GDNF Versus Artemin", P. Carmillo, E. Day, A. Rossomando, L. Walus et al., R. Cate, D. Sah and A. Whitty. Biochemistry, 44, 2545-2554, (2005).

  “Selectivity of BAFF/BLyS and APRIL for Binding to the TNF Family Receptors BAFF-R/BR3 and BCMA”, Eric Day, Teresa Cachero, Fang Qian, Yaping Sun, Dingyi Wen, Marc Pelletier, Yen-Ming Hsu and Adrian Whitty. Biochemistry, 44, 1919-1931, (2005).

• “Adopting a Practical Statistical Approach for Evaluating Assay Agreement in Drug Discovery”, D. Sun, A. Whitty, J. Papadatos, M. Newman, J. Donnelley, S.Bowes and S. Josiah. J. Biomolec. Screen., 10, 508-516, (2005).

  "Slow Binding Inhibition of InhA, the Enoyl Reductase from Mycobacterium Tuberculosis by the INH-NAD Adduct: Adduct Affinity is Insensitive to Mutations that Confer Drug Resistance" R. Rawat, A. Whitty and P.J. Tonge. Proc. Nat’l Acad. Sci. USA, 100, 13881-13886 (2003).

  "Comparison of Soluble Decoy IgG Fusion Proteins of BAFF-R and BCMA as Antagonists for BAFF" M. Pelletier, J.S. Thompson, F. Qian, S.A. Bixler, D. Gong, T. Cachero, K. Gilbride, E. Day, M. Zafari, C. Benjamin, L. Gorelik, A. Whitty, S.L. Kalled, C. Ambrose, and Y-M Hsu. J. Biol. Chem. 278, 33127-33133 (2003).

  "Stereoselectivity of Enoyl-CoA Hydratase Results from Preferential Activation of One of Two Bound Substrate Conformers" A.F. Bell, Y. Feng, H.A. Hofstein, S. Parikh, J. Wu, M.J. Rudolph, C. Kisker, A. Whitty and P.J. Tonge. Chem. Biol., 9, 1247-1255 (2002).

  “Effect of Divalent Cations on the Affinity and Selectivity of a4 Integrins Towards the Integrin Ligands VCAM-1 and MAdCAM-1: Ca2+ Activation of Integrin a4b1 Confers a Distinct Ligand Specificity”, Eric Day, Laurilee Osborne and Adrian Whitty. Cell Commun. Adhes., 9 205-219 (2002).

  "Comparative Assessment of the Ligand and Metal Ion Binding Properties of Integrins a9b1 and a4b1." R.B. Pepinsky, R.A. Mumford, L.L. Chen, D. leone, S.E. Amo, G. Van Riper, A. Whitty, B. Dolinski, R.R. Lobb, D.C. Dean, L.L. Chang, C.E. Raab, Q. Si, W.K. Hagmann, and R.B. Lingham. Biochemistry, 41, 7125-7141, (2002).

  "Comparison of Gene Expression Patterns Induced by Treatment of Human Umbilical Vein Endothelial Cells with IFN-a2b vs. IFN-b1a: Understanding the Functional Relationship Between Distinct Type I Interferons That Act Through a Common Receptor" A. Da Silva, M. Brickelmeier, G.R. Majeau, A.V. Lukashin, J. Peyman, A. Whitty and P.S. Hochman. J. Int. Cytokine Res. 22, 173-188 (2002).

  "The Immunological Synapse and CD28-CD80 Interactions" S.K. Bromley, A. Iaboni, S.J. davis, A. Whitty, J.M. Green, A.S. Shaw, A. weiss and M.L. Dustin. Nature Immunol. 2, 1159-1166 (2001).

  "Evidence that Ligand and Metal Ion Binding to Integrin a4b1 are Regulated through a Coupled Equilibrium." L.L. Chen, A. Whitty, D. Scott, W-C. Lee, M. Cornobise, S.P. Adams, R. Petter, R.R. Lobb and R.B. Pepinsky. J. Biol. Chem. 276, 36520-36529 (2001).

  "Mapping of IFN-b Epitopes Important for Receptor Binding and Activation: Comparison of Results Achieved Using Antibody-Based methods and Alanine Scanning Mutagenesis" L. Runkel, C. deDios, M. Karpusas, D. Baker, Z. Li, M. Zafari, M. Betzenhauser, P.N. Redlich, S.E. Grossberg, A. Whitty and P.S. Hochman. J. Int. Cytokine Res. 21, 931-941 (2001).

  "Enhanced Potency of Human Sonic Hedgehog by Hydrophobic Modification", F. Taylor, D. Wen, E. Garber, D. Baker, R. Arduini, K. Williams, P. Weinreb, P. Rayhorn, X. Hronowski, A. Whitty, E. Day, A. Boriack-Sjodin, R. Shapiro, A. Galdes and R.B.Pepinsky Biochemistry 40, 4359-4371 (2001).

  “Application of Linear Free Energy Relationships to the Serpin-Proteinase Inhibition Mechanism" P. Nash, G. McFadden and A. Whitty, FEBS Lett. 475 1-6 (2000).

  “Systematic Mutational Mapping of Sites on Human Interferon-b-1a that are Important for Receptor Binding and Functional Activity”, Laura Runkel, Carole deDios, Michael Karpusas, Matthew Betzenhauser, Celine Muldowney, Mohammad Zafari, Christopher D. Benjamin, Stephan Miller, Paula S. Hochman, and Adrian Whitty Biochemistry 39, 2538-2551 (2000).

  “Zinc-Dependent Structural Stability of Human Sonic Hedgehog”, Eric S. Day, Dingyi Wen, Ellen A. Garber, Jin Hong, Lena S. Avedissian, Paula Rayhorn, Weihong Shen, Adrian Whitty and Darren P. Baker. Biochemistry 38, 14868-14880 (1999).

  “Low Affinity Binding of an LFA-3/IgG1 Fusion Protein to CD2+ Cells is Independent of Cell Activation”, Gerard R. Majeau, Adrian Whitty, Kalvin Yim, Werner Meier and Paula S. Hochman. Cell Adhes. Commun. 7, 267-279 (1999).

  “ELISA Methods for the Analysis of Anti-IFN-b Antibody Responses Induced in Multiple Sclerosis Patients Treated with Recombinant Interferon-b”, Margot Brickelmeier, Rem Baciu, Betty Chao, Julio H. Cuervo, Paula Hochman and Adrian Whitty. J. Immunol. Methods. 227, 121-135 (1999).

  “Multiple Activation States of Integrin a4b1 detected Through Their Different Affinities for a Small Molecule Ligand”, Ling Ling Chen, Adrian Whitty, Roy R. Lobb, Steven P. Adams & R. Blake Pepinsky. J. Biol. Chem. 274, 13167-13175 (1999).

  “Small Molecule Cytokine Mimetics” Adrian Whitty and Christopher W. Borysenko. Chem. Biol. 6, R107-118 (1999).

  “Induced Fit Activation Mechanism of the Exceptionally Specific Serine Protease, Complement Factor D”, F. Taylor, S. Bixler, J. Budman, D. Wen, M. Karpusas, S. Ryan, G. Jaworski, S. Pollard and A. Whitty. Biochemistry 38, 2849-2859 (1999).

  “The Murine Anti-Human Common Gamma Chain Monoclonal Antibody CP.B8 blocks the Second step in the Formation of the Intermediate Affinity IL-2 Receptor”, Darren P. Baker, Adrian Whitty, Mohammed R. Zafari, Dian L. Olson, Catherine A. Hession, Konrad Miatkowski, Lena S. Avedissian, Susan F. Foley, Michele L. McKay, Christopher D. Benjamin and Linda C. Burkly. Biochemistry 37, 14337-14349 (1998).

  “The Structure of Human IFN-b: Implications for Activity”, Michael Karpusas, Adrian Whitty, Laura Runkel and Paula Hochman. Cellular and Molecular Life Science 54, 1203-1216 (1998).

  “Interaction Affinity Between Cytokine Receptor Components on the Cell Surface”, Adrian Whitty, Natalya Raskin, Dian Olson, Chris Borysenko, Christopher Benjamin and Linda Burkly. Proc. Nat’l Acad. Sci. USA. 95, 13165-13170 (1998).

  “Inhibitory Specificity of the Anti-Inflammatory Myxoma Virus Serpin, SERP-1”, P. Nash, A. Whitty, J. Macen, J. Handwerker and G. McFadden. J. Biol. Chem., 273, 20982-20991 (1998)

  “Structural Analysis of Human Interferon-b (IFN-b): Studies Addressing the Functional Differences between IFN-b-1a and IFN-b-1b.” Laura Runkel, Werner Maier, Blake Pepinsky, Michael Karpusas, Adrian Whitty, Kathleen Kimball, Margot Brickelmaier, Celine Muldowney, Wendy Jones and Susan Goelz. Pharm. Res. 15, 641-649 (1998)

  “Glial cell line-derived neurotrophic factor-dependent RET activation can be mediated by two different cell-surface accessory proteins”, M. Sanicola, C. Hession, D. Worley, P. Carmillo, C. Ehrenfels, L. Walus, S. Robinson, G. Jaworski, H. Wei, R. Tizard, A Whitty, R.B. Pepinsky and R.L. Cate; Proc. Nat’l Acad. Sci. USA, 94, 6238-6243 (1997)

  “Structure-Based Design of a Potent, selective, and Irreversible Inhibitor of the Catalytic Domain of the erbB Receptor Subfamily of Protein Tyrosine Kinases”, J. Singh, E.M. Dobrusin, D.W. Fry, T. Haske, A. Whitty and D.J. McNamara. J. Med. Chem., 40, 1130-1135 (1997).

  “A Direct Binding Assay for the Vascular Cell Adhesion Molecule-1 (VCAM-1) Interaction with a4 Integrins”, Roy R. Lobb, Giovanna Antognetti, R. Blake Pepinsky, Linda C. Burkly, Diane R. Leone and Adrian Whitty. Cell Adhesion and Communication, 3, 385-397 (1995).

  “Role of Binding Energy with Coenzyme A in Catalysis by 3–Oxoacid Coenzyme A Transferase”, Adrian Whitty, Carol A. Fierke & William P. Jencks. Biochemistry, 34, 11678-11689 (1995).

• In Preparation

  "Activation Mechanism of the GDNF Receptor Comprising the cRet Receptor Tyrosine Kinase and GDNF-Family Receptor (GFR)-a1", C. Borysenko, P. Carmillo, M. Zafari, S.Schlee, E. Day, A. Tse, L. Walus, V. Bailly, R. Cate and A. Whitty (Manuscript in preparation).

  “Pursuit of a Small Molecule Antagonist of TNFa through Fragment-Based Tethering®”, G. Kumaravel, A. Braisted, D. Cary, C. Vu, H. Peng, J. Dowling, I. Choong, G. Yao, J. Yoburn, J. Vessels, L. Cruz, L. Sha, P. Conlon, K. Van Vloten, L. Kabigting, I. Serafimova, M. Pellegrini, D. Waight, M. Taylor, D. Chin, E. Evensen, S. Miller, N. Viswanathan, J. Wang, S. Miller, S. Bowes, J. Wang, E. Day, E. Donis, J. Friedman, A. Fung, S. Josiah, J. Papadatos, D. Sun, M. He, T. Cachero, M. Cancilla, B. Cunningham and A. Whitty (Manuscript in preparation).

  “Crystal structure of Tumor Necrosis Factor (TNF)-a complexed with the TNF-R1 receptor”, L.F. Silvian, A. Arrieta, T.G. Cachero, I.M. Schwartz, E.S. Day, A. Corin, S. Miller, A.Whitty, and G.K. Farrington (Manuscript in preparation).

  “Coupling of Growth Factor Receptor Activation to Intracellular Signaling: Evidence for a ‘Counting’ Mechanism for cRet”, S. Schlee and A. Whitty (Manuscript in preparation).