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Vanderbilt-Ingram Cancer CenterVanderbilt-Ingram Cancer Center


Alex G. Waterson, Ph.D.

Research Assistant Professor of Pharmacology, Chemistry
VICC Member

Contact Information:

Vanderbilt University Medical Center
12410D MRB IV
Nashville, TN 37232-0697

Research Specialty

Oncology medicinal chemistry and drug discovery

Research Description

My interests lie in the application of synthetic organic chemistry to questions of biological importance. I been engaged for the last decade in medicinal chemistry toward primarily oncology related drug discovery efforts. Previous experience with the pharmaceutical industry included a key role in the discovery of dabrafenib, currently in Phase III clinical trials for the treatment of B-Raf positive metastatic melanoma.

Currently, I lead the medicinal chemistry team of the Fesik cancer drug discovery group. We employ fragment based drug discovery techniques to discover inhibitors of "undruggable" protein-protein interactions that are important for the future discovery of cancer therapeutics. The team evaluates and optimizes hits from NMR-based fragment screens as well as HTS campaigns toward such proteins. Using concepts of structure-based drug design, we seek to grow these fragments hits and/or link them together to synthesize optimized inhibitor molecules. These molecules may become the basis for cancer drugs in the future.

  • Jones, PL, Pask, GM, Romaine, IM, Taylor, RW, Reid, PR, Waterson, AG, Sulikowski, GA, Zwiebel, LJ Allosteric antagonism of insect odorant receptor ion channels. PLoS One, 7(1), e30304, 2012.
  • Sun, Q, Burke, JP, Phan, J, Burns, MC, Olejniczak, ET, Waterson, AG, Lee, T, Rossanese, OW, Fesik, SW Discovery of small molecules that bind to K-Ras and inhibit Sos-mediated activation. Angew Chem Int Ed Engl, 51(25), 6140-3, 2012.
  • Vangamudi, B. ; Ayres, A. E. ; Burke, J. P. ; Waterson, A. G. ; Rossanese, O. W. ; Fesik, S. W. "Evaluation of TBK1 as a novel cancer target in the K-Ras pathway.." Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research. , Chicago, IL Mar 31-Apr4, 2012.
  • Delpire, E, Baranczak, A, Waterson, AG, Kim, K, Kett, N, Morrison, RD, Daniels, JS, Weaver, CD, Lindsley, CW Further optimization of the K-Cl cotransporter KCC2 antagonist ML077: development of a highly selective and more potent in vitro probe. Bioorg Med Chem Lett, 22(14), 4532-5, 2012.
  • Taylor, RW, Romaine, IM, Liu, C, Murthi, P, Jones, PL, Waterson, AG, Sulikowski, GA, Zwiebel, LJ Structure-Activity Relationship of a Broad-Spectrum Insect Odorant Receptor Agonist. ACS Chem Biol, 2012.
  • Stellwagen, JC, Adjabeng, GM, Arnone, MR, Dickerson, SH, Han, C, Hornberger, KR, King, AJ, Mook, RA, Petrov, KG, Rheault, TR, Rominger, CM, Rossanese, OW, Smitheman, KN, Waterson, AG, Uehling, DE Development of potent B-RafV600E inhibitors containing an arylsulfonamide headgroup. Bioorg Med Chem Lett, 21(15), 4436-40, 2011.
  • Stoops, SL, Pearson, AS, Weaver, C, Waterson, AG, Days, E, Farmer, C, Brady, S, Weaver, CD, Beauchamp, RD, Lindsley, CW Identification and optimization of small molecules that restore E-cadherin expression and reduce invasion in colorectal carcinoma cells. ACS Chem Biol, 6(5), 452-65, 2011.
  • Thorne, CA, Hanson, AJ, Schneider, J, Tahinci, E, Orton, D, Cselenyi, CS, Jernigan, KK, Meyers, KC, Hang, BI, Waterson, AG, Kim, K, Melancon, B, Ghidu, VP, Sulikowski, GA, LaFleur, B, Salic, A, Lee, LA, Miller, DM, Lee, E Small-molecule inhibition of Wnt signaling through activation of casein kinase 1α. Nat Chem Biol, 6(11), 829-36, 2010.
  • Laquere, S. ; Arnone, M. ; Moss, K. ; Yang, J. ; Fisher, K. ; Kane-Carson, L. ; Smitheman, K. ; Ward, J. ; Heidrich, B. ; Rheault, T. ; Adjebeng, G. ; Hornberger, K. ; Stellwagen, J. ; Waterson, A. ; Han, C. ; Mook, Jr. R. A. ; Uehling, D. ; King, A. J. "A selective Raf kinase inhibitor induces cell death and tumor regression of human cancer cell lines encoding R-Raf V600E mutation." AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, poster abstract B88, 2009.
  • Adams, J. L. ; Dickerson, S. H. ; Johnson, N. W. ; Kuntz, K. ; Petrov, K. ; Ralph, J. M. ; Rheault, T. R. ; Schaaf, G. ; Stellwagen, J. ; Tian, X. ; Uehling, D. E. ; Waterson, A. G. ; Wilson, B "Benzene sufonamide thiazole and oxazole compounds." PCT Int. Appl. , (WO 2009137391 A2), 2009.
  • Schaaf, G. M. ; Mukherjee, S. ; Waterson, A. G. "Conjugate addition of sodium methanesulfinate to vinyl pyridines and diazines for the synthesis of aliphatic sulfones." Tetrahedron Lett. , 501928-1933, 2009.
  • Adjabeng, G. M. ; Bifulco, N. ; Davis-Ward, R. G. ; Dickerson, S. H. ; Hornberger, K. H. ; Petrov, K. ; Rheault, T. R. ; Uehling, D. E. ; Waterson, A. G. "Preparation of thiazole and oxazole kinase inhibitors for cancer treatment." PCT Int. Appl. , WO2009076140 A12009.
  • Bhagwanth, S, Waterson, AG, Adjabeng, GM, Hornberger, KR Room-temperature Pd-catalyzed amidation of aryl bromides using tert-butyl carbamate. J Org Chem, 74(12), 4634-7, 2009.
  • Waterson, A. G. Delpire, E. ; Days, E. ; Lewis, M. ; Kim, K. ; Lindsley, C. W. ; Weaver, C. D. "Small molecule inhibitors of the KCC2 neuronal co-transporter." Gordon Research Conference on Natural Products, poster session, 2009.
  • Waterson, AG, Petrov, KG, Hornberger, KR, Hubbard, RD, Sammond, DM, Smith, SC, Dickson, HD, Caferro, TR, Hinkle, KW, Stevens, KL, Dickerson, SH, Rusnak, DW, Spehar, GM, Wood, ER, Griffin, RJ, Uehling, DE Synthesis and evaluation of aniline headgroups for alkynyl thienopyrimidine dual EGFR/ErbB-2 kinase inhibitors. Bioorg Med Chem Lett, 19(5), 1332-6, 2009.
  • Stevens, KL, Alligood, KJ, Alberti, JG, Caferro, TR, Chamberlain, SD, Dickerson, SH, Dickson, HD, Emerson, HK, Griffin, RJ, Hubbard, RD, Keith, BR, Mullin, RJ, Petrov, KG, Gerding, RM, Reno, MJ, Rheault, TR, Rusnak, DW, Sammond, DM, Smith, SC, Uehling, DE, Waterson, AG, Wood, ER Synthesis and stereochemical effects of pyrrolidinyl-acetylenic thieno[3,2-d]pyrimidines as EGFR and ErbB-2 inhibitors. Bioorg Med Chem Lett, 19(1), 21-6, 2009.
  • Adjabeng, G. M. ; Bifulco, N. ; Davis-Ward, R. G. ; Dickerson, S. H. ; Donaldson, K. H. ; Petrov, K. ; Rheault, T. R. ; Schaaf,. G. M. ; Stellwagen, J. C. ; Uehling, D. E. ; Waterson, A. G. "Thiazole and oxazole kinase inhibitors." PCT Int. Appl. , (WO2009032667 A1), 2009.
  • Wood, ER, Shewchuk, LM, Ellis, B, Brignola, P, Brashear, RL, Caferro, TR, Dickerson, SH, Dickson, HD, Donaldson, KH, Gaul, M, Griffin, RJ, Hassell, AM, Keith, B, Mullin, R, Petrov, KG, Reno, MJ, Rusnak, DW, Tadepalli, SM, Ulrich, JC, Wagner, CD, Vanderwall, DE, Waterson, AG, Williams, JD, White, WL, Uehling, DE 6-Ethynylthieno[3,2-d]- and 6-ethynylthieno[2,3-d]pyrimidin-4-anilines as tunable covalent modifiers of ErbB kinases. Proc Natl Acad Sci U S A, 105(8), 2773-8, 2008.
  • Hubbard, RD, Dickerson, SH, Emerson, HK, Griffin, RJ, Reno, MJ, Hornberger, KR, Rusnak, DW, Wood, ER, Uehling, DE, Waterson, AG Dual EGFR/ErbB-2 inhibitors from novel pyrrolidinyl-acetylenic thieno[3,2-d]pyrimidines. Bioorg Med Chem Lett, 18(21), 5738-40, 2008.
  • Kuntz, K. ; Uehling, D. E. ; Waterson, A. G. ; Emmitte, K. A. ; Stevens, K. ; Shotwell, J. B. ; Smith, S. C. ; Nailor, K. E. ; Salovich, J. M. ; Wilson, B. J. ; Cheung, M. ; Mook, R. A. ; Baum, E. W. ; Moorthy, G. "Imidazopyridine kinase inhibitors." U.S. Pat. Appl. Publ. , (US2008300242 A1), 2008.
  • Uehling, D. E. ; Hubbard, R. D. ; Waterson, A. G. ; Petrov, K. ; Bifulco, N. , Jr. ; Wilson, J. W. ; Badiang, J. G. ; Cheung, M. ; Yamabe, M. "Preparation of 3-(pyrimidin-4-yl)pyrazolo[1,5-a]pyridines as ErbB kinase inhibitors for treating neoplasm." PCT Int. Appl. , (WO2007067506), 2007.
  • Waterson, AG, Stevens, KL, Reno, MJ, Zhang, YM, Boros, EE, Bouvier, F, Rastagar, A, Uehling, DE, Dickerson, SH, Reep, B, McDonald, OB, Wood, ER, Rusnak, DW, Alligood, KJ, Rudolph, SK Alkynyl pyrimidines as dual EGFR/ErbB2 kinase inhibitors. Bioorg Med Chem Lett, 16(9), 2419-22, 2006.
  • Uehling, D. E. ; Stevens, K. L. ; Dickerson, S. H. ; Waterson, A. G. ; Harris, P. A. ; Sammond, D. M. ; Hubbard, R. D. ; Emerson, H. K. ; Wilson, J. W. "Preparation of 2-pyrimidinyl pyrazolopyridines as ErbB kinase inhibitors for treating neoplasm." PCT Int. Appl, (WO2006068826), 2006.
  • Reno, M. J. ; Stevens, K. L. ; Waterson, A. G. ; Zhang, Y. "Preparation of pyrimidine derivatives as ErbB kinase inhibitors." PCT Int. Appl, (WO2005016914), 2005.
  • Dickerson, S. H. ; Emerson, H. K. ; Hinkle, K. W. ; Hornberger, K. R. ; Sammond, D. M. ; Smith, S. ; Stevens, K. L. ; Hubbard, R. D. ; Petrov, K. G. ; Reno, M. J. ; Uehling, D. E. ; Waterson, A. G. "Preparation of thienopyrimidine derivatives as ErbB kinase inhibitors." PCT Int. Appl. , (WO2005007083), 2005.
  • Badiang, J. G. ; Dickerson, S. H. ; Donaldson, K. H. ; Hinkle, K. W. ; Hornberger, K. R. ; Petrov, K. G. ; Reno, M. J. ; Stevens, K. L. ; Uehling, D. E. ; Waterson, A. G. "Preparation of thienopyrimidines as inhibitors of ErbB kinases." PCT Int. Appl. , (WO2004112714), 2004.
  • Padwa, A. ; Waterson, A. G. "A novel synthesis of polysubstituted phenols using the SnAr reaction of 2,5-dinitrofuran.”." ARKIVOC, 429-42, 2001.
  • Waterson, A. G. ; Meyers, A. I. "Studies directed toward the synthesis of Viridenomycin. Route 2: a second-generation approach." Tetrahedron Lett. , 424305-4308, 2001.
  • Waterson, AG, Meyers, AI Bicyclic lactams as chiral homoenolate equivalents: synthesis of (-)-penienone. J Org Chem, 65(21), 7240-3, 2000.
  • Padwa, A, Waterson, AG Studies dealing with thionium ion promoted mannich cyclization reactions. J Org Chem, 65(1), 235-44, 2000.
  • Padwa, A. ; Waterson, A. G. "Synthesis of nitrogen heterocycles using the intramolecular Pummerer reaction." Curr. Org. Chem, 4175-203, 2000.
  • Padwa, A. ; Waterson, A. G. "The thionium/N-acyliminium ion cyclization cascade as a strategy for the synthesis of azapolycyclic ring systems." Tetrahedron, (56), 10159-10173, 2000.
  • Padwa, A. ; Dimitroff, M. ; Waterson, A. G. ; Wu, T. "IMDAF cycloaddition as a method for the preparation of pyrrolophenanthridine alkaloids." J. Org. Chem. , 638585-8588, 1998.
  • Padwa, A. ; Waterson, A.G. "Synthesis of the perhydroindolizine nucleus by a Pummerer/Mannich induced cyclization cascade." Tetrahedron Lett. , 393986-3997, 1998.
  • Padwa, A. ; Dimitroff, M. ; Waterson, A. G. ; Wu, T. "Diels-Alder reaction of 2-amino-substituted furans as a method for preparing substituted anilines." J. Org. Chem. , 624088-4096, 1997.