The overall long-term goal of this program project application is to discover novel drugs for the treatment of cancer based on disrupting aberrant signal transduction pathways. In human cancers many components of signal transduction pathways are hyperactivated including the phosphatase SHP2 and the GTPase Ras which activate the serine/threonine kinase Raf which in turn binds, phosphorylates and inactivates the tumor suppressor pRb. Other components of signal transduction that are aberrant are those that allow tumors to evade apoptosis and include inactivation of the tumor suppressor p53 by binding the oncoprotein mdm2, overexpression of the anti-apoptotic Bel proteins, and sustained degradation of the proapoptotic proteins Baxand 1KB by the proteasome. These aberrant signal transduction pathways are intimately involved in oncogenesis and have been associated with poor prognosis, resistance to chemotherapy and shortened patient survival time. The central hypothesis upon which this program project is based is that disruption of mdm2/p53, Raf/Rb and Bcl/Bax associations and inhibition of SHP2 and proteasome activities will induce apoptosis and inhibit malignant transformation and tumor growth in human cancer cells. Five highly integrated and interrelated projects and 3 cores will work very closely together towards the overall goal of the P01. Chemists from each project will use structure-based rational design to prepare chemical libraries that will be evaluated by the high throughput screening (HTS) core to identify disrupters of mdm2/p53 (Project 1), Raf/Rb (Project 2), and Bcl/Bax (Project 4) and inhibitors of the proteasome (Project 3) and SHP2 (Project 5). Hits from these screens as well as those from HTS of commercially available chemical libraries will be evaluated by biologists from all 5 projects for potency and selectivity. The results from these structure activity relationship studies will then be fed back to the chemists of all 5 projects for lead optimization. The highly potent and selective leads will then be evaluated for the mechanism by which they inhibit specific signaling pathways, cell proliferation and malignant transformation, promote apoptosis and suppress tumor growth in animal models, Every step of our drug discovery process from design and synthesis of combinatorial libraries, design of specific biochemical and molecular assays, to evaluation of antitumor activity in animals will be highly focused on the creation of pharmacological agents with the highest degree of selectivity towards human cancers with aberrantly activated specific* signal transduction pathways. Furthermore, identification by one project of compounds that are highly selective for one pathway will be used by other projects to determine the importance of crosstalk between the aberrant pathways and the contribution of each pathway alone and collectively to malignant transformation. The work described in this P01 application will enhance our understanding of the role of SHP2, proteasome, Bcl/Bax, Raf/Rb and mdm2/p53 in oncogenesis and ultimately will result in the discovery of novel anticancer drugs that will broaden the spectrum of human cancers that can be treated successfully.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-GRB-P (O4))
Program Officer
Ogunbiyi, Peter
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
H. Lee Moffitt Cancer Center & Research Institute
United States
Zip Code
Kazi, Aslamuzzaman; Ozcan, Sevil; Tecleab, Awet et al. (2014) Discovery of PI-1840, a novel noncovalent and rapidly reversible proteasome inhibitor with anti-tumor activity. J Biol Chem 289:11906-15
Ozcan, Sevil; Kazi, Aslamuzzaman; Marsilio, Frank et al. (2013) Oxadiazole-isopropylamides as potent and noncovalent proteasome inhibitors. J Med Chem 56:3783-805
Treviño, José G; Verma, Monika; Singh, Sandeep et al. (2013) Selective disruption of rb-raf-1 kinase interaction inhibits pancreatic adenocarcinoma growth irrespective of gemcitabine sensitivity. Mol Cancer Ther 12:2722-34
Ge, Yiyu; Kazi, Aslamuzzaman; Marsilio, Frank et al. (2012) Discovery and synthesis of hydronaphthoquinones as novel proteasome inhibitors. J Med Chem 55:1978-98
Davis, Rebecca; Pillai, Smitha; Lawrence, Nicholas et al. (2012) TNF-?-mediated proliferation of vascular smooth muscle cells involves Raf-1-mediated inactivation of Rb and transcription of E2F1-regulated genes. Cell Cycle 11:109-18
Kim, Young B; Balasis, Maria E; Doi, Kenichiro et al. (2012) Synthesis and evaluation of substituted hexahydronaphthalenes as novel inhibitors of the Mcl-1/BimBH3 interaction. Bioorg Med Chem Lett 22:5961-5
Johnson, Jackie L; Pillai, Smitha; Pernazza, Danielle et al. (2012) Regulation of matrix metalloproteinase genes by E2F transcription factors: Rb-Raf-1 interaction as a novel target for metastatic disease. Cancer Res 72:516-26
Doi, Kenichiro; Li, Rongshi; Sung, Shen-Shu et al. (2012) Discovery of marinopyrrole A (maritoclax) as a selective Mcl-1 antagonist that overcomes ABT-737 resistance by binding to and targeting Mcl-1 for proteasomal degradation. J Biol Chem 287:10224-35
Li, X; Gilkes, D; Li, B et al. (2012) Abnormal MDMX degradation in tumor cells due to ARF deficiency. Oncogene 31:3721-32
Win-Piazza, Hla; Schneeberger, Valentina E; Chen, Liwei et al. (2012) Enhanced anti-melanoma efficacy of interferon alfa-2b via inhibition of Shp2. Cancer Lett 320:81-5

Showing the most recent 10 out of 39 publications