Fesik Lab

Medicinal Chemistry

Alex G. Waterson, Ph.D. is a Research Assistant Professor of Pharmacology and Chemistry and a medicinal chemist in the Fesik lab for cancer drug discovery.  He is interested in the application of synthetic and medicinal chemistry to questions of biological interest.  He joined Vanderbilt in 2008 as the Director of the Vanderbilt Institute of Chemical Biology Chemical Synthesis Core and subsequently joined the group of Professor Stephen Fesik the following year.  Alex earned his Ph.D. in Chemistry in 1999 at Emory University in Atlanta, Georgia under the direction of Professor Albert Padwa and completed his formal training as a postdoctoral research fellow at Colorado State University in the group of the late Professor Albert I. Meyers.  In 2001, Alex joined the medicinal chemistry department at GlaxoSmithKline in the Research Triangle Park area of North Carolina, where he contributed to the development of a new series of (unexpectedly) covalent modifying inhibitors of the ErbB family of kinases for the treatment of breast cancers and discovered a novel chemical series that led to a bRaf kinase drug candidate. This molecule is currently being evaluated in Phase III clinical trials for melanoma.  Along with managing a triple inhibitor kinase backup project and a target validation stage program, he also became active in an oncology-based new target initiative and was involved in the proposal and initiation of kinase and non-kinase targets important at the intersection of inflammation and oncology signaling pathways and in the Wnt pathway. Alex received numerous awards and recognitions for his work at GlaxoSmithKline, including thirteen GSK R&D awards and an Exceptional Science Award.  Along the way, Alex developed a significant expertise in the evaluation of the physical properties of inhibitors and the use of calculated properties to drive molecular design. Alex is a member of the American Chemical Society and the American Association of Cancer Research and serves on the Scientific Advisory Board of Cumberland Emerging Technologies.  He also serves as a reviewer for the Journal of Organic Chemistry and BioOrganic and Medicinal Chemistry Letters.  Within Vanderbilt, Alex is a member of the VICB operating committee and Co-Principal Investigator of the Vanderbilt Chemical Diversity Center, an entry in the National Cancer Institute’s Chemical Biology Consortium.

Faculty Profile

Publications and Patents:

1.  “Small molecule inhibition of Wnt signaling through activation of Casein Kinase 1 alpha” Thorne, C. A.; Schneider, J.; Tahinci, E.; Orton, D.; Cselenyi, C. S.; Jernigan, K. K.; Hanson, A., J.; Meyers, K. C.; Hang, B. I.; Waterson; A. G.; LaFleur, B.; Salic, A.; Lee, L. A.; Miller, III, D. M.; Lee, E. Nature Chemical Biology (submitted).

2.  “Benzene sulfonamide thiazole and oxazole compounds” 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. WO 2009137391 PCT Int. Appl. (2009), WO 2009137391 A2.

3.  “Preparation of thiazole and oxazole kinase inhibitors for cancer treatment” 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.  PCT Int. Appl. (2009),    301pp. WO2009076140 A1.

4.  “Room-temperature Pd-catalyzed amidation of aryl bromides using tert-butyl carbamate” Bhagwanth, S.; Waterson, A. G.; Adjabeng, G. M.; Hornberger, K. R. J. Org. Chem. 2009, 74, 4634-4637.

5.  “Conjugate addition of sodium methanesulfinate to vinyl pyridines and diazines for the synthesis of aliphatic sulfones: Schaaf, G. M.; Mukherjee, S.; Waterson, A. G. Tetrahedron Lett. 2009, 50, 1928-1933.

6.  “Thiazole and oxazole kinase inhibitors” 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.  PCT Int. Appl. (2009),    278pp. WO2009032667 A1.

7.  “Synthesis and evaluation of novel aniline headgroups for thienopyrimidine-based covalent dual EGFR/ErbB2 kinase inhibitors” Waterson, A. G.; Petrov,L. P.; Hornberger, K. R.; Hubbard, R. D.; Sammond, D. M.; Smith, S. C.; Hinkle, K. W.; Uehling, D. E.; Dickerson, S. H.; Rusnak, D. W.; Spehar, G. M.; Wood, E. R.; Griffin, R. J.; Kitrinos, N. P. Biorg. Med. Chem. Lett. 2009, 19, 1332-1336.

8.  “Synthesis and stereochemical effects of pyrrolidyl-acetylenic thieno[3,2-d]pyrimidines as EGFR and ErbB-2 inhibitors” Stevens, K. L; Alligood, K. J.; Alberti,  J. G. B.; Caferro, T. R.; Chamberlain, S. D.; Dickerson, S. H.; Disckson, H. D.; Emerson, H. K.; Griffin, R. J.; Hubbard, R. D.; Keith, B. R.; Mullin, R. J.; Petrov, K. G.; Gerding, R. M.; Reno, M. J.; Rheault, T. R.; Rusnak, D. W.; Sammond, D. M.; Smith, S. C.; Uehling, D. E.; Waterson, A. G.; Wood, E. R. Biorg. Med. Chem. Lett. 2009, .21-26.
9.  “Imidazopyridine kinase inhibitors”   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..   U.S. Pat. Appl. Publ.  (2008), 249pp.  US2008300242  A1.

10.  “Dual EGFR/ ErbB-2 inhibitors from novel pyrrolidinyl-acetylenic thieno[3,2-d]pyrimidines” Hubbard, R. D.; Dickerson, S. D.; Emerson, H. K.; Griffin, R. J.; Reno, M. J.; Hornberger, K. R.; Rusnak, D. W.; Wood, E. R.; Uehling, D. E.; Waterson, A. G. Biorg. Med. Chem. Lett. 2008, 18, 5738-5740.

11.  “6-Ethynylthieno[3,2-d]- and 6-Ethynylthieno[2,3-d]pyrimidin-4-anilines as tunable covalent modifiers of ErbB family receptor tyrosine kinases” Wood, E. R.; Shewchuck, L. M.; Ellis, B.; Brignola, P.; Brashear, R. L.; Caferro, T. R.; Dickerson, S. H.; Donaldson, K. H.; Gaul, M.; Griffen, R. J.; Hassell, A. M.; Keith, B.; Mullin, R.; Petrov, K., G.; Rusnak, D. W.; Tadepalli, S. M.; Ulrich, J. C.; Wagner, C. D.; Vanderwall, D. E.; Waterson, A. G.; White, W. L.; Uehling, D. E. Proc. Natl. Acad. Sci. 2008, 105, 2773-2778.

12.  “Preparation of 3-(pyrimidin-4-yl)pyrazolo[1,5-a]pyridines as ErbB kinase inhibitors for treating neoplasm” Uehling, D. E.; Hubbard, R. D.; Waterson, A. G.; Petrov, K.; Bifulco, N. , Jr.; Wilson, J. W.; Badiang, J. G.; Cheung, M.; Yamabe, M..  PCT Int. Appl.  (2007),  205pp.  WO2007067506.

13.  “Preparation of 2-pyrimidinyl pyrazolopyridines as ErbB kinase inhibitors for treating neoplasm”  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.  PCT Int. Appl.  (2006),  255 pp.  WO2006068826.

14.  “Alkynyl pyrimidines as dual EGFR/ErbB2 kinase inhibitors” Waterson, A. G; Stevens, K. L.; Reno, M. J.; Zhang. Y. –M.; Boros, E. E.; Bouvier, F.; Rastagar, A.; Uehling, D. U.; Dickerson, S. H.; Reep, B.; McDonald, O. B.; Wood, E. R.; Rusnak, D. W.; Alligood, K.; Rudolph, S. Biorg. Med. Chem. Lett. 2006, 16, 2419-2422.

15.  “Preparation of thienopyrimidine derivatives as ErbB kinase inhibitors.”  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.  PCT Int. Appl.  (2005),  241 pp.  WO2005007083.

16.  “Preparation of pyrimidine derivatives as ErbB kinase inhibitors.”  Reno, M. J.; Stevens, K. L.; Waterson, A. G.; Zhang, Y.  PCT Int. Appl.  (2005),  132 pp WO2005016914.

17.  “Preparation of thienopyrimidines as inhibitors of ErbB kinases.”  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.    PCT Int. Appl.  (2004),  103 pp  WO2004112714.

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

19.  “Studies directed toward the synthesis of Viridenomycin. Route 2: a second-generation approach.” Waterson, A. G.; Meyers, A. I. Tetrahedron Lett. 2001, 42, 4305-4308.

20.  “The thionium/N-acyliminium ion cyclization cascade as a strategy for the synthesis of azapolycyclic ring systems.”  Padwa, A.; Waterson, A. G. Tetrahedron 2000, 56, 10159-10173.

21.  “Bicyclic lactams as chiral homoenolate equivalents: Synthesis of (-)-Penienone.” Waterson, A. G.; Meyers, A. I. J. Org. Chem. 2000, 65, 7240-7243.

22.  “Synthesis of nitrogen heterocycles using the intramolecular Pummerer reaction.” Padwa, A.; Waterson, A. G. Curr. Org. Chem. 2000, 4, 175-203.

23.  “Studies dealing with thionium ion promoted Mannich cyclization reactions.” Padwa, A.; Waterson, A. G. J. Org. Chem. 2000, 65, 235-244.

24.  “Synthesis of the perhydroindolizine nucleus by a Pummerer/Mannich induced cyclization cascade.” Padwa, A.; Waterson, A.G. Tetrahedron Lett. 1998, 39, 8585-8588.

25.  “IMDAF cycloaddition as a method for the preparation of pyrrolophenanthridine alkaloids.” Padwa, A.; Dimitroff, M.; Waterson, A. G.; Wu, T. J. Org. Chem. 1998, 63, 3986-3997.

26.  “Diels-Alder reaction of 2-amino-substituted furans as a method for preparing substituted anilines.” Padwa, A.; Dimitroff, M.; Waterson, A. G.; Wu, T. J. Org. Chem. 1997, 62, 4088-4096.