Keywords
Last Name

Adrian Whitty, PhD

TitleAssociate Professor
InstitutionBoston University College of Arts and Sciences
DepartmentChemistry
Address590 Commonwealth Avenue
Boston MA 02215
Phone(617) 353-2488
Fax(617) 353-6466
 Research Expertise & Professional Interests
Professor Whitty received his Ph.D. in Organic Chemistry in 1991 from the University of Illinois at Chicago, followed by postdoctoral work with William P. Jencks at Brandeis University. Prior to joining the Boston University faculty in 2008, Adrian Whitty worked for 14 years at Biogen Idec (then Biogen Inc.). He rose from staff Scientist to the position of Director in the Drug Discovery Department and Head of Physical Biochemistry, leading a department that encompassed Quantitative Biochemistry, Assay Development and Compound Profiling, Structural Biology, and Molecular Modeling. During his time at Biogen Idec Prof. Whitty participated in or led multiple drug discovery project teams. He also maintained an active research program in the areas of receptor signaling and protein-ligand binding. He additionally directed the Biogen Idec Postdoctoral Program, developing a sterling reputation as a post-doctoral mentor.

The Whitty Group studies protein-protein and protein-ligand recognition, with an emphasis on how binding energy from these intermolecular interactions can be utilized to achieve biological function or inhibition. We apply this research in two distinct areas: (i) developing a quantitative, mechanistic understanding of the activation and signaling of growth factor receptors, and (ii) advancing our ability to discover drugs that inhibit protein-protein interactions.

Activation and signaling mechanisms in growth factor receptor systems: This work aims to address longstanding mechanistic questions concerning exactly how the binding of a cytokine or growth factor brings about an activated state of its receptor, and how the assembly of the activated receptor complex is quantitatively coupled to proximal and distal signaling events and to the ultimate cellular response (See Schlee et al., Nature Chemical Biology, 2006).

Discovery and characterization of small molecule (i.e. synthetic organic) inhibitors of protein-protein interactions: We aim to develop new approaches to this difficult problem, based on achieving a better understanding of what structural and physicochemical properties at protein-protein interfaces are important for inhibitor binding, and what kinds of novel chemical structures are best suited to exploit these features. Projects in this area are carried out in collaboration multiple other groups encompassing computational chemistry (Prof. Vajda), organic synthesis (Profs. Porco, Beeler, CMLD-BU; Prof. Pollastri, Northeastern U.), X-ray crystallography (Prof. Allen) and Biology (Prof. Gilmore, BU Department of Biology).

Techniques & Resources:

Development and implementation of biochemical and cell-based assays using state-of-the art technologies such as FRET, Time-Resolved Fluorescence, and Fluorescence Polarization.

Biophysical methods – the lab is equipped with a Biacore 3000 surface plasmon resonance (SPR) instrument for measuring protein-ligand binding in real time. Other biophysical methods used include fluorescence, analytical ultracentrifugation (AUC), dynamic lightscattering (DLS) and isothermal titration calorimetry (ITC).

Mammalian Cell Culture – the lab has a dedicated Tissue Culture facility equipped with laminar flow biosafety cabinet, cell incubators, centrifuge, Nikon inverted microscope, and liquid nitrogen cell storage system.

Specialized techniques for cell analysis (e.g. flow cytometry using a Becton-Dickinson FACSCaliburTM)

Quantitative data analysis, curve fitting and reaction pathway modeling using a variety of software packages including site licenses to MathematicaTM and MatLab®.

 Publications
Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
List All   |   Timeline
  1. Whitty A, Zhong M, Viarengo L, Beglov D, Hall DR, Vajda S. Quantifying the chameleonic properties of macrocycles and other high-molecular-weight drugs. Drug Discov Today. 2016 May; 21(5):712-7. PMID: 26891978.
    View in: PubMed
  2. Hall DR, Kozakov D, Whitty A, Vajda S. Lessons from Hot Spot Analysis for Fragment-Based Drug Discovery. Trends Pharmacol Sci. 2015 Nov; 36(11):724-36. PMID: 26538314.
    View in: PubMed
  3. Kozakov D, Hall DR, Napoleon RL, Yueh C, Whitty A, Vajda S. New Frontiers in Druggability. J Med Chem. 2015 Dec 10; 58(23):9063-88. PMID: 26230724.
    View in: PubMed
  4. Vajda S, Whitty A, Kozakov D. Fragments and hot spots in drug discovery. Oncotarget. 2015 Aug 7; 6(22):18740-1. PMID: 26300051.
    View in: PubMed
  5. Whitty A. A Particularly Discriminating Receptor. Cell Syst. 2015 Jul 29; 1(1):14-5. PMID: 27135685.
    View in: PubMed
  6. Kozakov D, Hall DR, Jehle S, Jehle S, Luo L, Ochiana SO, Jones EV, Pollastri M, Allen KN, Whitty A, Vajda S. Ligand deconstruction: Why some fragment binding positions are conserved and others are not. Proc Natl Acad Sci U S A. 2015 May 19; 112(20):E2585-94. PMID: 25918377.
    View in: PubMed
  7. Yeo AT, Chennamadhavuni S, Whitty A, Porco JA, Gilmore TD. Inhibition of Oncogenic Transcription Factor REL by the Natural Product Derivative Calafianin Monomer 101 Induces Proliferation Arrest and Apoptosis in Human B-Lymphoma Cell Lines. Molecules. 2015; 20(5):7474-94. PMID: 25915462.
    View in: PubMed
  8. Li S, Bhave D, Chow JM, Riera TV, Schlee S, Rauch S, Atanasova M, Cate RL, Whitty A. Quantitative analysis of receptor tyrosine kinase-effector coupling at functionally relevant stimulus levels. J Biol Chem. 2015 Apr 17; 290(16):10018-36. PMID: 25635057.
    View in: PubMed
  9. Whitty A, Zhou L. Horses for courses: reaching outside drug-like chemical space for inhibitors of challenging drug targets. Future Med Chem. 2015; 7(9):1093-5. PMID: 26132520.
    View in: PubMed
  10. Zhou L, Yeo AT, Ballarano C, Weber U, Allen KN, Gilmore TD, Whitty A. Disulfide-mediated stabilization of the I?B kinase binding domain of NF-?B essential modulator (NEMO). Biochemistry. 2014 Dec 23; 53(50):7929-44. PMID: 25400026.
    View in: PubMed
  11. Villar EA, Beglov D, Chennamadhavuni S, Porco JA, Kozakov D, Vajda S, Whitty A. How proteins bind macrocycles. Nat Chem Biol. 2014 Sep; 10(9):723-31. PMID: 25038790.
    View in: PubMed
  12. Cote SM, Gilmore TD, Shaffer R, Weber U, Bollam R, Golden MS, Glover K, Herscovitch M, Ennis T, Allen KN, Whitty A. Mutation of nonessential cysteines shows that the NF-?B essential modulator forms a constitutive noncovalent dimer that binds I?B kinase-ß with high affinity. Biochemistry. 2013 Dec 23; 52(51):9141-54. PMID: 24266532.
    View in: PubMed
  13. Day ES, Capili AD, Borysenko CW, Zafari M, Whitty A. Determining the affinity and stoichiometry of interactions between unmodified proteins in solution using Biacore. Anal Biochem. 2013 Sep 1; 440(1):96-107. PMID: 23711722.
    View in: PubMed
  14. Golden MS, Cote SM, Sayeg M, Zerbe BS, Villar EA, Beglov D, Sazinsky SL, Georgiadis RM, Vajda S, Kozakov D, Whitty A. Comprehensive experimental and computational analysis of binding energy hot spots at the NF-?B essential modulator/IKKß protein-protein interface. J Am Chem Soc. 2013 Apr 24; 135(16):6242-56. PMID: 23506214.
    View in: PubMed
  15. Day ES, Cote SM, Whitty A. Binding efficiency of protein-protein complexes. Biochemistry. 2012 Nov 13; 51(45):9124-36. PMID: 23088250.
    View in: PubMed
  16. Atanasova M, Whitty A. Understanding cytokine and growth factor receptor activation mechanisms. Crit Rev Biochem Mol Biol. 2012 Nov-Dec; 47(6):502-30. PMID: 23046381.
    View in: PubMed
  17. Zerbe BS, Hall DR, Vajda S, Whitty A, Kozakov D. Relationship between hot spot residues and ligand binding hot spots in protein-protein interfaces. J Chem Inf Model. 2012 Aug 27; 52(8):2236-44. PMID: 22770357.
    View in: PubMed
  18. Kozakov D, Hall DR, Chuang GY, Cencic R, Brenke R, Grove LE, Beglov D, Pelletier J, Whitty A, Vajda S. Structural conservation of druggable hot spots in protein-protein interfaces. Proc Natl Acad Sci U S A. 2011 Aug 16; 108(33):13528-33. PMID: 21808046.
    View in: PubMed
  19. Whitty A. Growing PAINS in academic drug discovery. Future Med Chem. 2011 May; 3(7):797-801. PMID: 21644825.
    View in: PubMed
  20. Silvian LF, Friedman JE, Strauch K, Cachero TG, Day ES, Qian F, Cunningham B, Fung A, Sun L, Shipps GW, Su L, Zheng Z, Kumaravel G, Whitty A. Small molecule inhibition of the TNF family cytokine CD40 ligand through a subunit fracture mechanism. ACS Chem Biol. 2011 Jun 17; 6(6):636-47. PMID: 21417339.
    View in: PubMed
  21. Singh J, Petter RC, Baillie TA, Whitty A. The resurgence of covalent drugs. Nat Rev Drug Discov. 2011 Apr; 10(4):307-17. PMID: 21455239.
    View in: PubMed
  22. di Clemente N, Jamin SP, Lugovskoy A, Carmillo P, Ehrenfels C, Picard JY, Whitty A, Josso N, Pepinsky RB, Cate RL. Processing of anti-mullerian hormone regulates receptor activation by a mechanism distinct from TGF-beta. Mol Endocrinol. 2010 Nov; 24(11):2193-206. PMID: 20861221.
    View in: PubMed
  23. Whitty A, Gelb MH. Critical challenges and emerging paradigms in drug discovery. Curr Opin Chem Biol. 2010 Aug; 14(4):437-9. PMID: 20621548.
    View in: PubMed
  24. Arkin MR, Whitty A. The road less traveled: modulating signal transduction enzymes by inhibiting their protein-protein interactions. Curr Opin Chem Biol. 2009 Jun; 13(3):284-90. PMID: 19553156.
    View in: PubMed
  25. Pollastri MP, Whitty A, Merrill JC, Tang X, Ashton TD, Amar S. Identification and characterization of kava-derived compounds mediating TNF-alpha suppression. Chem Biol Drug Des. 2009 Aug; 74(2):121-8. PMID: 19538508.
    View in: PubMed
  26. Whitty A. Cooperativity and biological complexity. Nat Chem Biol. 2008 Aug; 4(8):435-9. PMID: 18641616.
    View in: PubMed
  27. Whitty A, Riera TV. New ways to target old receptors. Curr Opin Chem Biol. 2008 Aug; 12(4):427-33. PMID: 18570899.
    View in: PubMed
  28. Dustin ML, Starr T, Coombs D, Majeau GR, Meier W, Hochman PS, Douglass A, Vale R, Goldstein B, Whitty A. Quantification and modeling of tripartite CD2-, CD58FC chimera (alefacept)-, and CD16-mediated cell adhesion. J Biol Chem. 2007 Nov 30; 282(48):34748-57. PMID: 17911103.
    View in: PubMed
  29. Schlee S, Carmillo P, Whitty A. Quantitative analysis of the activation mechanism of the multicomponent growth-factor receptor Ret. Nat Chem Biol. 2006 Nov; 2(11):636-44. PMID: 17013378.
    View in: PubMed
  30. Whitty A, Kumaravel G. Between a rock and a hard place? Nat Chem Biol. 2006 Mar; 2(3):112-8. PMID: 16484997.
    View in: PubMed
  31. Cachero TG, Schwartz IM, Qian F, Day ES, Bossen C, Ingold K, Tardivel A, Krushinskie D, Eldredge J, Silvian L, Lugovskoy A, Farrington GK, Strauch K, Schneider P, Whitty A. Formation of virus-like clusters is an intrinsic property of the tumor necrosis factor family member BAFF (B cell activating factor). Biochemistry. 2006 Feb 21; 45(7):2006-13. PMID: 16475789.
    View in: PubMed
  32. Baker DP, Lin EY, Lin K, Pellegrini M, Petter RC, Chen LL, Arduini RM, Brickelmaier M, Wen D, Hess DM, Chen L, Grant D, Whitty A, Gill A, Lindner DJ, Pepinsky RB. N-terminally PEGylated human interferon-beta-1a with improved pharmacokinetic properties and in vivo efficacy in a melanoma angiogenesis model. Bioconjug Chem. 2006 Jan-Feb; 17(1):179-88. PMID: 16417267.
    View in: PubMed
  33. He MM, Smith AS, Oslob JD, Flanagan WM, Braisted AC, Whitty A, Cancilla MT, Wang J, Lugovskoy AA, Yoburn JC, Fung AD, Farrington G, Eldredge JK, Day ES, Cruz LA, Cachero TG, Miller SK, Friedman JE, Choong IC, Cunningham BC. Small-molecule inhibition of TNF-alpha. Science. 2005 Nov 11; 310(5750):1022-5. PMID: 16284179.
    View in: PubMed
  34. Sun D, Whitty A, Papadatos J, Newman M, Donnelly J, Bowes S, Josiah S. Adopting a practical statistical approach for evaluating assay agreement in drug discovery. J Biomol Screen. 2005 Aug; 10(5):508-16. PMID: 16093560.
    View in: PubMed
  35. Carmillo P, Dagø L, Day ES, Worley DS, Rossomando A, Walus L, Orozco O, Buckley C, Miller S, Tse A, Cate RL, Rosenblad C, Sah DW, Grønborg M, Whitty A. Glial cell line-derived neurotrophic factor (GDNF) receptor alpha-1 (GFR alpha 1) is highly selective for GDNF versus artemin. Biochemistry. 2005 Feb 22; 44(7):2545-54. PMID: 15709767.
    View in: PubMed
  36. Day ES, Cachero TG, Qian F, Sun Y, Wen D, Pelletier M, Hsu YM, Whitty A. Selectivity of BAFF/BLyS and APRIL for binding to the TNF family receptors BAFFR/BR3 and BCMA. Biochemistry. 2005 Feb 15; 44(6):1919-31. PMID: 15697217.
    View in: PubMed
  37. Rawat R, Whitty A, Tonge PJ. The isoniazid-NAD adduct is a slow, tight-binding inhibitor of InhA, the Mycobacterium tuberculosis enoyl reductase: adduct affinity and drug resistance. Proc Natl Acad Sci U S A. 2003 Nov 25; 100(24):13881-6. PMID: 14623976.
    View in: PubMed
  38. Pelletier M, Thompson JS, Qian F, Bixler SA, Gong D, Cachero T, Gilbride K, Day E, Zafari M, Benjamin C, Gorelik L, Whitty A, Kalled SL, Ambrose C, Hsu YM. Comparison of soluble decoy IgG fusion proteins of BAFF-R and BCMA as antagonists for BAFF. J Biol Chem. 2003 Aug 29; 278(35):33127-33. PMID: 12796483.
    View in: PubMed
  39. Bell AF, Feng Y, Hofstein HA, Parikh S, Wu J, Rudolph MJ, Kisker C, Whitty A, Tonge PJ. Stereoselectivity of enoyl-CoA hydratase results from preferential activation of one of two bound substrate conformers. Chem Biol. 2002 Nov; 9(11):1247-55. PMID: 12445775.
    View in: PubMed
  40. Day ES, Osborn L, Whitty A. Effect of divalent cations on the affinity and selectivity of alpha4 integrins towards the integrin ligands vascular cell adhesion molecule-1 and mucosal addressin cell adhesion molecule-1: Ca2+ activation of integrin alpha4beta1 confers a distinct ligand specificity. Cell Commun Adhes. 2002 Jul-Aug; 9(4):205-19. PMID: 12699089.
    View in: PubMed
  41. Pepinsky RB, Mumford RA, Chen LL, Leone D, Amo SE, Riper GV, Whitty A, Dolinski B, Lobb RR, Dean DC, Chang LL, Raab CE, Si Q, Hagmann WK, Lingham RB. Comparative assessment of the ligand and metal ion binding properties of integrins alpha9beta1 and alpha4beta1. Biochemistry. 2002 Jun 4; 41(22):7125-41. PMID: 12033947.
    View in: PubMed
  42. da Silva AJ, Brickelmaier M, Majeau GR, Lukashin AV, Peyman J, Whitty A, Hochman PS. Comparison of gene expression patterns induced by treatment of human umbilical vein endothelial cells with IFN-alpha 2b vs. IFN-beta 1a: understanding the functional relationship between distinct type I interferons that act through a common receptor. J Interferon Cytokine Res. 2002 Feb; 22(2):173-88. PMID: 11911800.
    View in: PubMed
  43. Bromley SK, Iaboni A, Davis SJ, Whitty A, Green JM, Shaw AS, Weiss A, Dustin ML. The immunological synapse and CD28-CD80 interactions. Nat Immunol. 2001 Dec; 2(12):1159-66. PMID: 11713465.
    View in: PubMed
  44. Runkel L, De Dios C, Karpusas M, Baker D, Li Z, Zafari M, Betzenhauser M, Muldowney C, Miller S, Redlich PN, Grossberg SE, Whitty A, Hochman PS. Mapping of IFN-beta epitopes important for receptor binding and biologic activation: comparison of results achieved using antibody-based methods and alanine substitution mutagenesis. J Interferon Cytokine Res. 2001 Nov; 21(11):931-41. PMID: 11747625.
    View in: PubMed
  45. Chen LL, Whitty A, Scott D, Lee WC, Cornebise M, Adams SP, Petter RC, Lobb RR, Pepinsky RB. Evidence that ligand and metal ion binding to integrin alpha 4beta 1 are regulated through a coupled equilibrium. J Biol Chem. 2001 Sep 28; 276(39):36520-9. PMID: 11473127.
    View in: PubMed
  46. Taylor FR, Wen D, Garber EA, Carmillo AN, Baker DP, Arduini RM, Williams KP, Weinreb PH, Rayhorn P, Hronowski X, Whitty A, Day ES, Boriack-Sjodin A, Shapiro RI, Galdes A, Pepinsky RB. Enhanced potency of human Sonic hedgehog by hydrophobic modification. Biochemistry. 2001 Apr 10; 40(14):4359-71. PMID: 11284692.
    View in: PubMed
  47. Nash P, McFadden G, Whitty A. Application of linear free energy relationships to the serpin-proteinase inhibition mechanism. FEBS Lett. 2000 Jun 09; 475(1):1-6. PMID: 10854846.
    View in: PubMed
  48. Runkel L, deDios C, Karpusas M, Betzenhauser M, Muldowney C, Zafari M, Benjamin CD, Miller S, Hochman PS, Whitty A. Systematic mutational mapping of sites on human interferon-beta-1a that are important for receptor binding and functional activity. Biochemistry. 2000 Mar 14; 39(10):2538-51. PMID: 10704203.
    View in: PubMed
  49. Day ES, Wen D, Garber EA, Hong J, Avedissian LS, Rayhorn P, Shen W, Zeng C, Bailey VR, Reilly JO, Roden JA, Moore CB, Williams KP, Galdes A, Whitty A, Baker DP. Zinc-dependent structural stability of human Sonic hedgehog. Biochemistry. 1999 Nov 09; 38(45):14868-80. PMID: 10555969.
    View in: PubMed
  50. Brickelmaier M, Hochman PS, Baciu R, Chao B, Cuervo JH, Whitty A. ELISA methods for the analysis of antibody responses induced in multiple sclerosis patients treated with recombinant interferon-beta. J Immunol Methods. 1999 Jul 30; 227(1-2):121-35. PMID: 10485260.
    View in: PubMed
  51. Chen LL, Whitty A, Lobb RR, Adams SP, Pepinsky RB. Multiple activation states of integrin alpha4beta1 detected through their different affinities for a small molecule ligand. J Biol Chem. 1999 May 07; 274(19):13167-75. PMID: 10224072.
    View in: PubMed
  52. Whitty A, Borysenko CW. Small molecule cytokine mimetics. Chem Biol. 1999 Apr; 6(4):R107-18. PMID: 10099129.
    View in: PubMed
  53. Taylor FR, Bixler SA, Budman JI, Wen D, Karpusas M, Ryan ST, Jaworski GJ, Safari-Fard A, Pollard S, Whitty A. Induced fit activation mechanism of the exceptionally specific serine protease, complement factor D. Biochemistry. 1999 Mar 02; 38(9):2849-59. PMID: 10052957.
    View in: PubMed
  54. Majeau GR, Whitty A, Yim K, Meier W, Hochman PS. Low affinity binding of an LFA-3/IgG1 fusion protein to CD2+ T cells is independent of cell activation. Cell Adhes Commun. 1999; 7(3):267-79. PMID: 10626910.
    View in: PubMed
  55. Karpusas M, Whitty A, Runkel L, Hochman P. The structure of human interferon-beta: implications for activity. Cell Mol Life Sci. 1998 Nov; 54(11):1203-16. PMID: 9849615.
    View in: PubMed
  56. Whitty A, Raskin N, Olson DL, Borysenko CW, Ambrose CM, Benjamin CD, Burkly LC. Interaction affinity between cytokine receptor components on the cell surface. Proc Natl Acad Sci U S A. 1998 Oct 27; 95(22):13165-70. PMID: 9789059.
    View in: PubMed
  57. Baker DP, Whitty A, Zafari MR, Olson DL, Hession CA, Miatkowski K, Avedissian LS, Foley SF, McKay ML, Benjamin CD, Burkly LC. 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. Biochemistry. 1998 Oct 13; 37(41):14337-49. PMID: 9772159.
    View in: PubMed
  58. Nash P, Whitty A, Handwerker J, Macen J, McFadden G. Inhibitory specificity of the anti-inflammatory myxoma virus serpin, SERP-1. J Biol Chem. 1998 Aug 14; 273(33):20982-91. PMID: 9694848.
    View in: PubMed
  59. Runkel L, Meier W, Pepinsky RB, Karpusas M, Whitty A, Kimball K, Brickelmaier M, Muldowney C, Jones W, Goelz SE. Structural and functional differences between glycosylated and non-glycosylated forms of human interferon-beta (IFN-beta). Pharm Res. 1998 Apr; 15(4):641-9. PMID: 9587963.
    View in: PubMed
  60. Sanicola M, Hession C, Worley D, Carmillo P, Ehrenfels C, Walus L, Robinson S, Jaworski G, Wei H, Tizard R, Whitty A, Pepinsky RB, Cate RL. Glial cell line-derived neurotrophic factor-dependent RET activation can be mediated by two different cell-surface accessory proteins. Proc Natl Acad Sci U S A. 1997 Jun 10; 94(12):6238-43. PMID: 9177201.
    View in: PubMed
  61. Singh J, Dobrusin EM, Fry DW, Haske T, Whitty A, McNamara DJ. Structure-based design of a potent, selective, and irreversible inhibitor of the catalytic domain of the erbB receptor subfamily of protein tyrosine kinases. J Med Chem. 1997 Mar 28; 40(7):1130-5. PMID: 9089334.
    View in: PubMed
  62. Lobb RR, Antognetti G, Pepinsky RB, Burkly LC, Leone DR, Whitty A. A direct binding assay for the vascular cell adhesion molecule-1 (VCAM1) interaction with alpha 4 integrins. Cell Adhes Commun. 1995 Dec; 3(5):385-97. PMID: 8640376.
    View in: PubMed
  63. Whitty A, Fierke CA, Jencks WP. Role of binding energy with coenzyme A in catalysis by 3-oxoacid coenzyme A transferase. Biochemistry. 1995 Sep 19; 34(37):11678-89. PMID: 7547900.
    View in: PubMed
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