John S. Lazo
The pharmacological mechanism of action of small molecules and on the fundamental biological role of protein tyrosine phosphatases in disease.
Our laboratory is currently focused on two major topics: (1) discovering and characterizing novel small molecules that could lead to treatments of cancer, Alzheimer’s disease, ionizing radiation exposure and neglected diseases, and (2) validating the fundamental biological role of protein tyrosine phosphatases in cancer.
We use a variety of platforms to seek new small molecules for human disease. These include computational modeling, high throughput target-based in vitro screening and phenotypic screening of small molecule and small interfering RNA libraries. We maintain several automated liquid handling devices and small molecule libraries for the purpose of exploring various areas of chemical space for bioactive compounds. We have been using human pluripotent cells as a model for radiation injury and mitigation.
A second major research project focuses on investigating how the dual specificity, protein tyrosine phosphatases, such as Cdc25B and phosphatase of regenerating liver PTP4A3, control cell proliferation, migration, invasion, and survival using both molecular biological and pharmacological approaches and on applying chemical biological methodologies to the discovery of new chemical probes and potential therapeutics. We currently have developed the first well-characterized, conditional PTP4A3 knockout mouse model to investigate the role of this unique protein in colorectal tumorigenesis and tumor angiogenesis. We are seeking to identify the endogenous substrates for PTP4A3 in tumor and endothelial cells using proteomic and informatics approaches. We have discovered several potent and specific small molecule inhibitors of these protein phosphatases and are investigating their pharmacological properties.
Targeted deletion of the metastasis-associated phosphatase Ptp4a3 (PRL-3) suppresses murine colon cancer. Zimmerman, M.W., Homanics, G.E. and Lazo, J.S. PLoS One, 8:e58300 (2013).
Effector kinase coupling enables high-throughput screens for direct HIV-1 Nef antagonists with antiretroviral activity. Emert-Sedlak, L.A., Narute, P., Shu, S.T., Poe, J.A., Shi, H., Yanamala, N., Alvarado, J.J., Lazo, J.S., Yeh, J.I., Johnston, P.A., and Smithgall, T.E. Chem Biol. 20:82-91 (2013).
Phenotypic screening reveals topoisomerase I as a breast cancer stem cell therapeutic target. Zhang,F., Rothermund, K, Gangadharan, S.B., Pommier, Y., Prochownik, E.V., and Lazo, J.S. Oncotarget. 3:998-1010 (2012).
Alkylation sensitivity screens reveal a conserved cross-species functionome. Svilar, D., Dyavaiah, M., Brown, A.R., Tang, J., McDonald, P.R., Shun, T. Y., Wang, X-H., Lazo, J.S., Pollack, I.F., Begley, T.J. and Sobol, R. W. Mol Cancer Res., 11:1683-1692 (2012).
Discovery of diverse small molecule chemotypes with cell-based PKD1 inhibitory activity. Sharlow, E.R., Mustata Wilson, G., Close, D., Leimgruber, S., Tandon, M., Reed, R.B., Shun, T.Y., Wang, Q.J., Wipf, P., and Lazo, J.S. PLoS One 6:e25134 (2011).
Compound acquisition and prioritization algorithm for constructing structurally diverse compound libraries. Ma, C., Lazo, J.S, and Xie, X.Q. ACS Comb Sci. 13:223-231 (2011).