Stephen W. Fesik, Ph.D.

Stephen W. Fesik, Ph.D.

Professor of Biochemistry, Pharmacology, and Chemistry, Orrin H. Ingram, II Chair in Cancer Research

634-A RRB
23rd & Pierce Avenue
Nashville, TN 37232
(615) 322-6303

Mailing Address:  2215 Garland Ave., 607 Light Hall, Nashville, TN 37232-0146
Office:                   634-A  Robinson Research Building
Laboratory:           802/804  Robinson Research Building
Office Phone:        615-322-6303
Fax:                       615-875-3236

Faculty Profile

Principal Investigator (BRET Faculty Member)
Member, Vanderbilt Institute of Chemical Biology (VICB)
Member, Vanderbilt Ingram Cancer Center (VICC)
Member, Center for Structural Biology (CSB)

Stephen W. Fesik, Ph.D. is the Orrin H. Ingram, II Chair in Cancer Research and a Professor of Biochemistry, Pharmacology, and Chemistry in Vanderbilt University School of Medicine. He is also a member of the Vanderbilt Ingram Cancer Center (VICC), the Vanderbilt Institute of Chemical Biology (VICB) and the Center for Structural Biology (CSB). The focus of his research is on cancer drug discovery using fragment-based approaches and structure-based drug design. Prior to joining Vanderbilt in May 2009, Dr. Fesik was the Divisional Vice President of Cancer Research at Abbott (2000-2009) where he built a pipeline of compounds that are showing promising anti-cancer activities in early stage clinical trials. In addition, while he was at Abbott, he developed several new NMR methods, determined the three-dimensional structures of several proteins and protein/ligand complexes, pioneered a method for drug discovery called SAR by NMR, and applied this method to identify and optimize ligands for binding to many protein drug targets. His research has also involved the use of siRNA for target identification and target validation. Dr. Fesik has published more than 240 papers, trained 38 postdoctoral fellows, has been a reviewer for the NIH Biophysical Chemistry Study Section and the NCI Experimental Therapeutics (NExT) Program, and has served as a member of the Editorial Boards of the Journal of Medicinal Chemistry, Journal of Biomolecular NMR, Biophysical Journal, Molecular Cell, Chemical Biology & Drug Design, ChemMedChem, Molecular Cancer Therapeutics, Oncogene, Combinatorial Chemistry and High Throughput Screening, and the Highlights Advisory Panel for Nature Reviews Cancer. He has served on the Keystone Scientific Advisory Board and Board of Directors and the Scientific Advisory Board of the UPenn Abramson Cancer Center. He is currently a member of Aileron Therapeutics SAB and the Bruker Board of Directors. He has obtained several awards, including the Chairman’s Award (1996), Outstanding Researcher of the Year Award (1997), and the Researcher of the Year Team Award (2008) from Abbott, the Servier Lecturer Award (1998) from the University of Montreal, the ASBMB-Fritz Lipmann Lectureship Award (1999), the Lifetime Achievement Award in Nuclear Magnetic Resonance from EAS (2003), the SBS Technology Innovation Award (2010), the NIH Director's Pioneer Award (2010), the Fellow of the American Association for the Advancement of Science (AAAS) (2010), and the AACR Award for Outstanding Achievement in Chemistry in Cancer Research (2012).


Click here to view a current list of Dr. Fesik's PubMed publications.

Selected Publications

Fesik, S.W.  Isotope-edited NMR spectroscopy.  Nature, 232, 865-866 (1988).
Fesik, S.W. and E.R.P. Zuiderweg.  Heteronuclear three dimensional NMR spectroscopy.  A strategy for the simplification of homonuclear two dimensional NMR spectra.  J. Magn. Reson., 78, 588-593 (1988).
Fesik, S.W., R.T. Gampe, Jr., T.F. Holzman, D.A. Egan, R. Edalji, J.R. Luly, R. Simmer, and R. Helfrich. Isotope-edited NMR of cyclosporin A bound to cyclophilin:  Evidence for a trans 9,10 amide bond.  Science, 250, 1406-1409 (1990).
Zuiderweg, E.R.P., A.M. Petros, S.W. Fesik, and E.T. Olejniczak. Four-dimensional [13C,1H,13C,1H]HMQC-NOE-HMQC NMR spectroscopy:  Resolving tertiary NOE distance constraints in the spectra of larger proteins.  J. Am. Chem. Soc., 113,  370-372 (1991).
Theriault, Y., T.M. Logan, R. Meadows, L. Yu, E. T. Olejniczak, T.F. Holzman, R.L. Simmer, and S.W. Fesik.  Solution structure of the cyclosporin A/cyclophilin complex by NMR.  Nature, 361, 88-91 (1993).
Yoon, H.S., P.J. Hajduk, A.M. Petros, E.T. Olejniczak, R.P. Meadows, and S.W. Fesik. Solution structure of a pleckstrin homology domain. Nature, 369, 672-675 (1994). 
Harlan, J.E., P.J. Hajduk, H.S. Yoon, and S.W. Fesik.  Pleckstrin homology domains bind to phosphatidylinositol 4,5-bisphosphate. Nature, 371, 167-170 (1994). 
Zhou, M.-M., K.S. Ravichandran, E.T. Olejniczak, A.M. Petros, R.P. Meadows, M. Sattler, J.E. Harlan, W.S. Wade, S.J. Burakoff, and S.W. Fesik.  Structure and ligand recognition of the phosphotyrosine binding domain of Shc.  Nature, 378, 584-592 (1995).
Muchmore, S.W., M. Sattler, H. Liang, R.P. Meadows, J.E. Harlan, H.S. Yoon, D. Nettesheim, B.S. Chang, C.B. Thompson, S.-L. Wang, S.-C. Ng, and S.W. Fesik.  X-ray and NMR structure of human Bcl-XL, an inhibitor of programmed cell death.  Nature, 381, 335-341 (1996).
Shuker, S.B., P.J. Hajduk, R.P. Meadows, and S.W. Fesik.  Discovering high-affinity ligands for proteins:  SAR by NMR.  Science, 274, 1531-1534 (1996).
Huang, B., M. Eberstadt, E.T. Olejniczak, R.P. Meadows, and S.W. Fesik.  NMR structure and mutagenesis of the Fas (APO-1/CD95) death domain.  Nature, 384, 638-641 (1996).
Minn, A. J., P. Velez, S. L. Schendel, H. Liang, S. W. Muchmore, S. W. Fesik, M. Fill, and C. B. Thompson. Bcl-xL forms an ion channel in synthetic lipid membranes.  Nature, 385, 353-357 (1997).
Sattler, M., H. Liang, D. Nettesheim, R.P. Meadows, J.E. Harlan, M. Eberstadt, H. Yoon, S.B. Shuker, B. Chang, A.J. Minn, C.B. Thompson, and S.W. Fesik.  Structure of Bcl-xL/Bak peptide complex: Recognition between regulators of apoptosis.  Science, 275, 983-986 (1997).
Hajduk, P. J., G. Sheppard, D. G. Nettesheim, E. T. Olejniczak, S. B. Shuker, R. P. Meadows, D. H. Steinman, G. M. Carrera, Jr., P. A. Marcotte, J. Severin, K. Walter, H. Smith, E. Gubbins, T. F. Holzman, D. W. Morgan, S. K. Davidsen, J. B. Summers, and S. W. Fesik.  Discovery of potent nonpeptide inhibitors of stromelysin using SAR by NMR.  J. Am. Chem. Soc., 119, 5818-5827 (1997).
Olejniczak, E. T., P. J. Hajduk, P. A. Marcotte, D. G. Nettesheim, R. P. Meadows, R. Edalji, T. F. Holzman, and S. W. Fesik.  Stromelysin inhibitors designed from weakly bound fragments:  Effects of linking and cooperativity.  J. Am. Chem. Soc., 119, 5828-5832 (1997).
Hajduk, P.J., J. Dinges, G.F. Miknis, M. Merlock, T. Middleton, D.J. Kempf, D.A. Egan, K.A. Walter, T. Robbins, S.B. Shuker, T.F. Holzman, and S.W. Fesik. NMR-based discovery of lead inhibitors that block DNA-binding of the human papillomavirus E2 protein.  J. Med. Chem., 40, 3144-3150 (1997).
Hajduk, P.J., E.T. Olejniczak,  and S.W. Fesik.  One dimensional relaxation- and diffusion-edited NMR methods for screening compounds that bind to macromolecules.  J. Am. Chem. Soc., 119, 12257-12261 (1997).
Hajduk, P.J., R.P. Meadows, and S.W. Fesik.  Discovering high-affinity ligands for proteins.  Science, 278, 497-499 (1997).
Eberstadt, M., B. Huang, Z. Chen, R. P. Meadows, S. Ng, L. Zheng, and S. W. Fesik.  NMR structure and mutagenesis of the FADD (Mort1) death-effector domain.  Nature, 392, 941-945 (1998).
Betz, S.F., A. Schnuchel, H. Wang, E.T. Olejniczak, R.P. Meadows, B.P. Lipsky, E.A.S. Harris, D.E. Staunton, and S.W. Fesik.  Solution structure of the cytohesin-1 (B2-1) Sec7 domain and its interaction with the GTPase ADP ribosylation factor 1.  Proc. Natl. Acad. Sci., USA, 95, 7909-7914 (1998).
Liu, X., H. Wang, M. Eberstadt, A. Schnuchel, E.T. Olejniczak, R.P. Meadows, J.M. Schkeryantz, D.A. Janowick, J.E. Harlan, E.A.S. Harris, D.E. Staunton, S.W. Fesik.  NMR structure and mutagenesis of the N-terminal Dbl homology domain of the nucleotide exchange factor Trio.  Cell, 95, 269-277 (1998).
Hajduk, P.J., J. Dinges, J. M. Schkeryantz, D. Janowick, M. Kaminski, M. Tufano, D. J. Augeri, A. Petros. V.  Nienaber, P. Zhong, R. Hammond, M. Coen, B. Beutel, L. Katz, and S. W. Fesik. Novel inhibitors of Erm methyltransferases from NMR and parallel synthesis.  J.   Med. Chem., 42, 3852-3859 (1999).
Sun, C., M. Cai, A. H. Gunasekera, R. P. Meadows, H. Wang, J. Chen, H. Zhang, W. Wu,  N. Xu, S.-C. Ng, and S. W. Fesik.  NMR structure and mutagenesis of the inhibitor of apoptosis protein XIAP.  Nature, 401,818-822 (1999).
Huth, J. R., E. T. Olejniczak, R. Mendoza, H. Liang, E. A. S. Harris, M. L. Lupher Jr., A. E. Wilson, S. W. Fesik, and D. E. Staunton.  NMR and mutagenesis evidence for an I domain allosteric site that regulates lymphocyte function-associated antigen 1 ligand binding. Proc. Natl. Acad. Sci., USA, 97, 5231-5236 (2000).
Hajduk, P. J., D. J. Augeri, J.Mack, R.  Mendoza, J. Yang, S. F. Betz,  and S. W. Fesik.  NMR-based screening of proteins containing 13C-labeled methyl groups. J. Am. Chem. Soc., 122, 7898-7904 (2000).
Fesik, S. W.  Insights into Programmed Cell Death through Structural Biology.  Cell, 103, 273-282 (2000).
Hajduk, P. J., S. Boyd, D.  Nettesheim, A. Rueter, V.  Nienaber, J.  Severin, R.  Smith,   D. Davidson, T.  Rockway, and S. W. Fesik.  The identification of novel inhibitors of urokinase  using NMR-based screening.  J. Med. Chem., 43, 3862-3866 (2000).
Hajduk, P. J., M. Bures, J.  Praestgaard, and S. W. Fesik.  Priviledged molecules for protein binding identified from NMR-based screening.  J. Med. Chem., 43, 3443-3447 (2000). 
H. Albert, Y. Guo, R. P. Meadows, M. Michaelides, S. K. Davidsen, and S. W. Fesik. NMR- Hajduk, P. J., A. Gomstyan, S. Didomenico, M. Cowart, E. K. Bayburt, L. Solomon, J. Severin, R. Smith, K. Walter, T. F. Holzman, A. Stewart, S. McGaraughty, M. F. Jarvis, E. Kowaluk, and S. W. Fesik.  Design of adenosine kinase inhibitors from the NMR-based screening of fragments.  J. Med. Chem., 43, 4781-4786 (2000).
Liu, Z., C. Sun, E. T. Olejniczak, R. P. Meadows, S. F. Betz, T. Oost, J. Herrman, J. C. Wu, and S. W. Fesik.  Structural basis for binding of Smac/DIABLO to the XIAP Bir3 domain.  Nature, 408, 1004-1008 (2000).
Petros, A. M., A. Medek, D. G. Netthesheim, D. H. Kim, H. Yoon, R. P. Meadows, K. Swift, E.D. Matayoshi, T. Oltersdorf, and S.W. Fesik.  Solution structure of the anti-apoptotic protein Bcl-2.  Proceed. Natl. Acad. Sci., USA, 98, 3012-3017 (2001).
Fesik, S. W., and Y. Shi.  Controlling the caspases.  Science, 294, 1477-1478 (2001).
Riedl S. J., M. Renatus, R. Schwarzenbacher, Q. Zhou, C. Sun, S. W. Fesik, R. C. Liddington, and G. S. Salvesen.  Structural basis for the inhibition of caspase-3 by XIAP.  Cell, 104, 791-800 (2001).
Hajduk, P. J., S. B. Shuker, D. G. Nettesheim, L. Xu, D. J. Augeri, D. Betebenner, R. Craig, D. based modification of matrix metalloproteinase inhibitors with improved bioavailability. J. Med. Chem., 45, 5628-5639 (2002).
Yu, L., T. K. Oost, J. M. Schkeryantz, J. Yang, D. Janowick, and S. W. Fesik.  Discovery of aminoglycoside mimetics by NMR-based screening of Escherichia coli A-site RNA.  J. Am. Chem. Soc., 125, 4444-4450 (2003).
Oost, T., C. Sun, R.C. Armstrong, A. Al-Assaad, S.F. Betz, T.L. Deckwerth, H. Ding, S.W. Elmore, R.P. Meadows, E.T. Olejniczak, A. Oleksijew, T. Oltersdorf, S.H. Rosenberg, A.R. Shoemaker, K.J. Tomaselli, H. Zou and S.W. Fesik.  Discovery of potent antagonists of the antiapoptotic protein XIAP for the treatment of cancer.  J. Med. Chem. 47, 4417-4426 (2004).
Oltersdorf, T., S.W. Elmore, A.R. Shoemaker, R.C. Armstrong, D.J. Augeri, B.A. Belli, M. Bruncko, T.L. Deckwerth, J. Dinges, P.J. Hajduk, M.K. Joseph, S. Kitada, S.J. Korsmeyer, A.R. Kunzer, A. Letai, C. Li, M.J. Mitten, D.G. Nettesheim, S. Ng, P.M. Nimmer, J.M. O’Connor, A. Oleksijew, A.M. Petros, J.C. Reed, W. Shen, S.K. Tahir, C.B. Thompson, K.J. Tomaselli, B. Wang, M.D. Wendt, H. Zhang, S.W. Fesik and S.H. Rosenberg.  An inhibitor of Bcl-2 family proteins induces regression of solid tumors.  Nature 435, 677-681 (2005).
Li, L., X. Lin, M. Staver, A. Shoemaker, D. Semizarov, S.W. Fesik and Y. Shen.  Evaluating hypoxia-inducible factor-1α as a cancer therapeutic target via inducible RNA interference in vivo.  Cancer Res. 65, 7249-7258 (2005).
Morgan-Lappe, S., K.W. Woods, Q. Li, M.G. Anderson, M. Schurdak, Y. Luo, V.L. Giranda, S.W. Fesik and J.D. Leverson.  RNAi-based screening of the human kinome identifies Akt-cooperating kinases:  A new approach to designing efficacious multi-targeted kinase inhibitors.  Oncogene 25, 1340-1348 (2006).
Fesik, S.W.  Promoting apoptosis as a strategy for cancer drug discovery.  Nature Rev. Cancer 5, 876-885 (2005).
Petros, A.M., J. Dinges, D.J. Augeri, S.A. Baumeister, D.A. Betebenner, M.G. Bures, S.W. Elmore, P.J. Hajduk, M.K. Joseph, S.K. Landis, D.G. Nettesheim, S.H. Rosenberg, W. Shen, S. Thomas, X. Wang, I. Zanze, H. Zhang and S.W. Fesik.  Discovery of a potent inhibitor of the antiapoptotic protein Bcl-XL from NMR and parallel synthesis.  J. Med Chem. 49, 656-663 (2006). 
Tahir, S.K., X. Yang, M.G. Anderson, S.E. Morgan-Lappe, A.Sarthy, J. Chen, R.B. Warner, S-C. Ng, S. Fesik, S. Elmore, S. Rosenberg, and C. Tse.  Influence of Bcl-2 family members on the cellular response of Small Cell Lung Cancer cell lines to ABT-737. Cancer Res. 67, 1176-1183 (2007).
Sarthy, A., S. Morgan-Lappe, D. Zakula, L. Vernetti, M. Schurdak, J. C.L. Packer, M. G. Anderson, S. Shirasawa, T. Sasazuki, and S.W. Fesik.  Survivin depletion preferentially reduces the survival of activated k-ras-transformed cells.  Mol. Cancer Ther. 6, 269-276 (2007).
Morgan-Lappe, S.E., X. Huang, L. Garcia, C. Zhang, A.V. Sarthy, D. Zakula, L. Vernetti, M. Schurdak, J. Wang, and S.W. Fesik.  Identification of Ras-related nuclear protein, targeting protein for xenopus kinesin-like protein 2, and stearoyl-CoA desaturase 1 as promising cancer targets from an RNAi-based screen. Cancer Res. 67, 4390-4398 (2007).
Tse, C., A.R. Shoemaker, J. Adickes, M.G. Anderson, J. Chen, S. Jin, E.F. Johnson, K.C. Marsh, M.J. Mitten, P. Nimmer, L. Roberts, S.K. Tahir, Y. Xiao, X. Yang, H. Zhang, S. Fesik, S.H. Rosenberg, and S.W. Elmore.  ABT-263:  a potent and orally bioavailable Bcl-2 family inhibitor.  Cancer Res.68, 3421-3428 (2008).
Shah O.J., Lin X., Li L., Huang X., Li J., Anderson M.G., Tang H., Rodriguez L.E., Warder S.E., McLoughlin S., Chen J., Palma J., Glaser K.B., Donawho C.K., Fesik S.W., Shen Y. Bcl-XL represents a druggable molecular vulnerability during aurora B inhibitor-mediated polyploidization. Proc. Natl. Acad. Sci., USA, 107, 12634-12639 (2010). PMC2906553
Petros A.M., Huth J.R., Oost T., Park C.M., Ding H., Wang X., Zhang H., Nimmer P., Mendoza R., Sun C., Mack J., Walter K., Dorwin S., Gramling E., Ladror U., Rosenberg S.H., Elmore S.W., Fesik S.W., Hajduk P.J. Discovery of a potent and selective Bcl-2 inhibitor using SAR by NMR. Bioorg. Med. Chem. Lett., 20, 6587-6591 (2010). 
Lin X., Li L., Wang R., Wilcox D., Zhao X., Song J., Huang X., Hansen T.M., Dande P., Wada C., Hubbard R.D., Kohlbrenner W.M., Fesik S.W., Shen Y. A robust in vivo positive-readout system for monitoring siRNA delivery to xenograft tumors. RNA, 17, 603-612. (2011).
Souza-Fagundes E.M., Frank A.O., Feldkamp M.D., Dorset D.C., Chazin W.J., Rossanese O.W., Olejniczak E.T., Fesik S.W. A high-throughput fluorescence polarization anisotropy assay for the 70N domain of Replication Protein A. Anal. Biochem., 421, 742–749 (2012). PMC3274598
Sun Q., Burke J.P., Phan J., Burns M.C., Olejniczak E.T., Waterson A.G., Lee T., Rossanese O.W., Fesik S.W. Discovery of small molecules that bind to K-Ras and inhibit Sos-mediated activation. Angew. Chem. Int. Ed. Engl., 51, 6140-6143 (2012).