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Vanderbilt-Ingram Cancer CenterVanderbilt-Ingram Cancer Center

 

Alex G. Waterson, Ph.D.

Research Assistant Professor of Pharmacology, Chemistry
Researcher

Contact Information:

Vanderbilt University Medical Center
802C RRB
Nashville, TN 37232-0697
615-322-9971

Profile

An accomplished and externally recognized medicinal chemist and scientific manager, I have directly impacted diverse projects within academia and the pharmaceutical industry and contributed to projects at all stages of the drug discovery process, including target identification and validation, lead optimization, and preclinical DMPK, efficacy, and toxicity optimization. 

Here at Vanderbilt, I have led and participated in hit discovery, hit-to-lead, and lead optimization campaigns for both fragment-based and HTS-derived compounds.
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An accomplished and externally recognized medicinal chemist and scientific manager, I have directly impacted diverse projects within academia and the pharmaceutical industry and contributed to projects at all stages of the drug discovery process, including target identification and validation, lead optimization, and preclinical DMPK, efficacy, and toxicity optimization. 

Here at Vanderbilt, I have led and participated in hit discovery, hit-to-lead, and lead optimization campaigns for both fragment-based and HTS-derived compounds. I am also the Scientific Coordinator and co-PI of Vanderbilt’s center within the NCI’s NExT consortium, which is charged with utilizing the collaborative resources of the consortium to discovery new drugs for novel cancer targets.

Prior to joining Vanderbilt, I was a member of a number of multidisciplinary teams charged with prosecuting cancer targets at GlaxoSmithKline. During this time I discovered the chemical series that led directly to the B-Raf inhibitor dabrafenib and was an integral member of a team that placed this molecule into clinical investigation.

Education

  •          1994 B.S. - Mississippi State University
  •          1999 Ph.D. - Emory University

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.

Publications
  • 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.