John S. Lazo
- AB, Johns Hopkins University
- PhD, University of Michigan
- Professor, Pharmacology
The mechanism of action of small molecules and the fundamental biological role of protein tyrosine phosphatases
The primary research focus of the Lazo Laboratory is on the mechanism of action and of resistance to novel and existing anticancer agents, particularly natural products, and on the fundamental biological role of protein tyrosine phosphatases.
We are currently studying small molecules that disrupt the interactions of the oncoprotein c-Myc with its partner Max to determine their usefulness as anticancer agents. We have developed a human tumor stem cell model that permits the interrogation of chemical libraries and small interference RNA libraries to identify compounds and pathways that control the survival of tumor stem cells. Similarly, we are studying small molecules and intracellular pathways that mitigate or enhance the toxic effects of radiation. Some of the high throughput approaches we use are broadly applicable to other pathological conditions including neurodegenerative diseases, such as Alzheimer's, and neglected diseases, such as leishmaniasis.
A second major research project focuses on investigating how protein tyrosine phosphatases, such as mitogen-activated protein kinase phosphatases, Cdc25, and phosphatase of regenerating liver, 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 phosphatase of regenerating liver knock out mouse model to investigate the role of this unique protein in tumorigenesis. We have discovered several potent and specific small molecule inhibitors of these protein phosphatases and are investigating their pharmacological properties.
- Cramer J, Zimmerman M, Thompson T, Homanics G, Lazo J, Lagasse E. Deletion of Ptp4a3 reduces clonogenicity and tumor-initiation ability of colitis-associated cancer cells in mice. Stem cell research. 2014;13(1): 164-71. PMID: 24950307 | PMCID: PMC4090270
- Emert-Sedlak L, Narute P, Shu S, Poe J, Shi H, Yanamala N, Alvarado J, Lazo J, Yeh J, Johnston P, Smithgall T. Effector kinase coupling enables high-throughput screens for direct HIV-1 Nef antagonists with antiretroviral activity. Chemistry & biology. 2013;20(1): 82-91. PMID: 23352142 | PMCID: PMC3559019
- Lazo J, Sharlow E, Epperly M, Lira A, Leimgruber S, Skoda E, Wipf P, Greenberger J. Pharmacologic profiling of phosphoinositide 3-kinase inhibitors as mitigators of ionizing radiation-induced cell death. The Journal of pharmacology and experimental therapeutics. 2013;347(3): 669-80. PMID: 24068833 | PMCID: PMC3836314
- Zimmerman M, Homanics G, Lazo J. Targeted deletion of the metastasis-associated phosphatase Ptp4a3 (PRL-3) suppresses murine colon cancer. PloS one. 2013;8(3): e58300. PMID: 23555575 | PMCID: PMC3610886
- Svilar D, Dyavaiah M, Brown A, Tang J, Li J, McDonald P, Shun T, Braganza A, Wang X, Maniar S, St Croix C, Lazo J, Pollack I, Begley T, Sobol R. Alkylation sensitivity screens reveal a conserved cross-species functionome. Molecular cancer research : MCR. 2012;10(12): 1580-96. PMID: 23038810 | PMCID: PMC3877719
- Zhang F, Rothermund K, Gangadharan S, Pommier Y, Prochownik E, Lazo J. Phenotypic screening reveals topoisomerase I as a breast cancer stem cell therapeutic target. Oncotarget. 2012;3(9): 998-1010. PMID: 22948175 | PMCID: PMC3660065
- Ma C, Lazo J, Xie X. Compound acquisition and prioritization algorithm for constructing structurally diverse compound libraries. ACS combinatorial science. 2011;13(3): 223-31. PMID: 21480665 | PMCID: PMC3909521
- Sharlow E, Mustata Wilson G, Close D, Leimgruber S, Tandon M, Reed R, Shun T, Wang Q, Wipf P, Lazo J. Discovery of diverse small molecule chemotypes with cell-based PKD1 inhibitory activity. PloS one. 2011;6(10): e25134. PMID: 21998636 | PMCID: PMC3187749