Alex G. Waterson, Ph.D.

Research Associate Professor

a.waterson@vanderbilt.edu

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Faculty Appointments
Research Associate Professor of Pharmacology Research Associate Professor in Chemistry
Education
Ph.D., Organic Chemistry, Emory University, Atlanta, GeorgiaB.S., Chemistry, Mississippi State University, Mississippi State, Mississippi
Office Address
2200 Pierce Ave South
Nashville, TN 37232-6600
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.
Research Keywords
Oncology medicinal chemistry and drug discovery
Publications
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 [print-electronic]. 2012 Oct 10/19/2012; 7(10): 1647-52. PMID: 22924767, DOI: 10.1021/cb300331z, ISSN: 1554-8937.

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 [print-electronic]. 2012 Jul 7/15/2012; 22(14): 4532-5. PMID: 22727639, PMCID: PMC3389279, PII: S0960-894X(12)00738-X, DOI: 10.1016/j.bmcl.2012.05.126, ISSN: 1464-3405.

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 [print-electronic]. 2012 Jun 6/18/2012; 51(25): 6140-3. PMID: 22566140, PMCID: PMC3620661, DOI: 10.1002/anie.201201358, ISSN: 1521-3773.

Vangamudi, B.; Ayres, A. E.; Burke, J. P.; Waterson, A. G.; Rossanese, O. W.; Fesik, S. W., editor.. Evaluation of TBK1 as a novel cancer target in the K-Ras pathway.

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 [print-electronic]. 2012; 7(1): e30304. PMID: 22272331, PMCID: PMC3260273, PII: PONE-D-11-19400, DOI: 10.1371/journal.pone.0030304, ISSN: 1932-6203.

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 [print-electronic]. 2011 Aug 8/1/2011; 21(15): 4436-40. PMID: 21733693, PII: S0960-894X(11)00804-3, DOI: 10.1016/j.bmcl.2011.06.021, ISSN: 1464-3405.

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 [print-electronic]. 2011 May 5/20/2011; 6(5): 452-65. PMID: 21241068, PMCID: PMC3401128, DOI: 10.1021/cb100305h, ISSN: 1554-8937.

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 1a. Nat. Chem. Biol [print-electronic]. 2010 Nov; 6(11): 829-36. PMID: 20890287, PMCID: PMC3681608, PII: nchembio.453, DOI: 10.1038/nchembio.453, ISSN: 1552-4469.

Bhagwanth S, Waterson AG, Adjabeng GM, Hornberger KR. Room-temperature Pd-catalyzed amidation of aryl bromides using tert-butyl carbamate. J. Org. Chem. 2009 Jun 6/19/2009; 74(12): 4634-7. PMID: 19518153, DOI: 10.1021/jo9004537, ISSN: 1520-6904.

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 [print-electronic]. 2009 Mar 3/1/2009; 19(5): 1332-6. PMID: 19208477, PII: S0960-894X(09)00081-X, DOI: 10.1016/j.bmcl.2009.01.080, ISSN: 1464-3405.

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., editor.. A selective Raf kinase inhibitor induces cell death and tumor regression of human cancer cell lines encoding R-Raf V600E mutation.

Waterson, A. G. Delpire, E.; Days, E.; Lewis, M.; Kim, K.; Lindsley, C. W.; Weaver, C. D., editor.. Small molecule inhibitors of the KCC2 neuronal co-transporter.

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 [print-electronic]. 2009 Jan 1/1/2009; 19(1): 21-6. PMID: 19028424, PII: S0960-894X(08)01392-9, DOI: 10.1016/j.bmcl.2008.11.023, ISSN: 1464-3405.

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. 2009; 50: 1928-33.

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 [print-electronic]. 2008 Nov 11/1/2008; 18(21): 5738-40. PMID: 18842405, PII: S0960-894X(08)01162-1, DOI: 10.1016/j.bmcl.2008.09.090, ISSN: 1464-3405.

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 [print-electronic]. 2008 Feb 2/26/2008; 105(8): 2773-8. PMID: 18287036, PMCID: PMC2268535, PII: 0708281105, DOI: 10.1073/pnas.0708281105, ISSN: 1091-6490.

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 [print-electronic]. 2006 May 5/1/2006; 16(9): 2419-22. PMID: 16483772, PII: S0960-894X(06)00153-3, DOI: 10.1016/j.bmcl.2006.01.111, ISSN: 0960-894X.

Padwa, A.; Waterson, A. G.. A novel synthesis of polysubstituted phenols using the SnAr reaction of 2,5-dinitrofuran.”. ARKIVOC. 2001; 4: 29-42.

Waterson, A. G.; Meyers, A. I.. Studies directed toward the synthesis of Viridenomycin. Route 2: a second-generation approach. Tetrahedron Lett. 2001; 42: 4305-8.

Waterson AG, Meyers AI. Bicyclic lactams as chiral homoenolate equivalents: synthesis of (-)-penienone. J. Org. Chem. 2000 Oct 10/20/2000; 65(21): 7240-3. PMID: 11031061, ISSN: 0022-3263.

Padwa A, Waterson AG. Studies dealing with thionium ion promoted mannich cyclization reactions. J. Org. Chem. 2000 Jan 1/14/2000; 65(1): 235-44. PMID: 10813921, PII: jo991414h, ISSN: 0022-3263.

Padwa, A.; Waterson, A. G.. The thionium/N-acyliminium ion cyclization cascade as a strategy for the synthesis of azapolycyclic ring systems. Tetrahedron. 2000; ((56)): 10159-73.

Padwa, A.; Waterson, A. G.. Synthesis of nitrogen heterocycles using the intramolecular Pummerer reaction [editorial]. Curr. Org. Chem. 2000; 4: 175-203.

Padwa, A.; Waterson, A.G.. Synthesis of the perhydroindolizine nucleus by a Pummerer/Mannich induced cyclization cascade. Tetrahedron Lett. 1998; 39: 3986-97.

Padwa, A.; Dimitroff, M.; Waterson, A. G.; Wu, T.. IMDAF cycloaddition as a method for the preparation of pyrrolophenanthridine alkaloids. J. Org. Chem. 1998; 63: 8585-8.

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. 1997; 62: 4088-96.