The focus of our lab is on cancer drug discovery using fragment-based approaches and structure-based design. To accomplish this goal, we have assembled a multidisciplinary team that includes structural biologists, medicinal chemists, and cell biologists. In our lab, we clone, express, and purify proteins, conduct fragment-based screens, determine the three-dimensional structures of protein/ligand complexes using NMR and/or X-ray crystallography, design and synthesize compounds, and test compounds in primary and secondary biological assays. The cancer drug targets that we are pursuing are highly validated but technically challenging such as K-Ras and c-Myc.
Thomas LR, Wang Q, Grieb BC, Phan J, Foshage AM, Sun Q, Olejniczak ET, Clark T, Dey S, Lorey S, Alicie B, Howard GC, Cawthon B, Ess KC,Eischen CM, Zhao Z, Fesik SW, Tansey WP. Interaction with WDR5 Promotes Target Gene Recognition and Tumorigenesis by MYC. Molecular Cell. 2015, pii: S1097-2765(15)00142-2. [Epub ahead of print]
Waterson AG, Kennedy JP, Patrone JD, Pelz NF, Feldkamp MD, Frank AO, Vangamudi B, Souza-Fagundes EM, Rossanese OW, Chazin WJ, Fesik SW. Diphenylpyrazoles as replication protein a inhibitors. ACS Medicinal Chemistry Letters. 2014, 6(2):140-5.
Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. Drugging the undruggable RAS: Mission possible? Nature Reviews Drug Discovery. 2014, 13(11):828-51.
Harner MJ, Chauder BA, Phan J, Fesik SW. Fragment-based screening of the bromodomain of ATAD2. Journal of Medicinal Chemistry. 2014, 57(22):9687-92l.
Belmar J, Fesik SW. Small molecule Mcl-1 inhibitors for the treatment of cancer.Pharmacology & Therapeutics. 2015, 145:76-84.
Frank, A.O., Vangamudi, B., Feldkamp, M.D., Souza-Fagundes, E.M., Luzwick, J.W., Cortez, D., Olejniczak, E.T., Waterson, A.G., Rossanese, O.W., Chazin, W.J., Fesik, S.W.Discovery of a Potent Stapled Helix Peptide That Binds to the 70N Domain of Replication Protein A. Journal of Medicinal Chemistry.2014, 0 (0): [Epub ahead of print].
Burns, M.C., Sun, Q., Daniels, R.N., Camper, D., Kennedy, J.P., Phan, J., Olejniczak, E.T., Lee, T., Waterson, A.G., Rossanese, O.W., Fesik, S.W. Approach for targeting Ras with small molecules that activate SOS-mediated nucleotide exchange. Proceedings of the National Academy of Sciences. 2014, 111 (9): 3401-6.
Friberg, A., Vigil, D., Zhao, B., Daniels, R.N., Burke, J.P., Garcia-Barrantes, P.M., Camper, D., Chauder, B.A., Lee, T., Olejniczak, E.T., Fesik, S.W. Discovery of Potent Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods and Structure-Based Design. Journal of Medicinal Chemistry. 2013, 56 (1): 15-30.
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.Angewandte Chemie-International Edition.2012, 51 (25): 6140-6143.
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. Analytical Biochemistry. 2012, 421 (2): 742-749.
Ackler, S. Mitten, M.J. Foster, K. Oleksijew, A. Refici, M. Tahir, S.K., Xiao, Y. Tse, C. Frost, D.J. Fesik, S.W. Rosenberg S.H., Elmore S.W., Shoemaker A.R. The Bcl-2 inhibitor ABT-263 enhances the response of multiple chemotherapeutic regimens in hematologic tumors in vivo. Cancer Chemotherapy and Pharmacology. 2010, 66 (5): 869-880.