Project 3 - Ronen MarmorsteinThe RAS-RAF-MEK-ERK (MARK) and PI3K-AKT signaling pathways are constitutively activated throughmultiple mechanisms in melanoma implicating the kinases in these pathways as important therapeutictargets. In particular, the BRAF kinase, part of the MARK pathway, plays an important role in melanoma asBRAF somatic mutations have been found in about two-thirds of malignant melanomas with the majority ofthese mutations resulting in elevated kinase activity from a V600E substitution in the kinase domain(BRAFV600E). In addition, members of our program project have found that 57% of melanomas have highlyamplified levels of wild-type BRAF. Within the PI3K/AKT signaling pathway, the AKT kinase, which isactivated by PISKa, is constitutively activated in most metastatic melanomas. Taken together, BRAF,BRAFV600E and PISKa are important oncoproteins associated with melanoma and are therefore attractivetargets for inhibition for melanoma treatment. Although, small molecule inhibitors for both BRAF and PISKahave been developed, they suffer from a lack of suitable potency and specificity.The overall goal of project 3 is to prepare improved BRAF-, BRAFV600E- and PISKa - specific inhibitors thatcan be used to specifically interrogate the RAS-RAF-MEK-ERK (MAPK) and PI3K-AKT signaling pathwaysin melanoma and that can be further developed into drugs for the treatment of melanoma.For our studies we will combine biochemical, chemical, structural and computational methodologies towardsthe structure-based design of kinase-type specific inhibitors with the following Specific Aims: (1) Developpotent and specific BRAF and BRAFV600E inhibitors, and (2) Develop potent and specific PISKag inhibitors.We have generated significant preliminary data supporting the feasibility of completing each of our aims andour studies will be highly synergistic with each of the other projects of the program to synthesize and screenfor novel organometallic BRAF, BRAFV600E and PISKa inhibitors (Project 4), and to test these inhibitorsusing complex in vitro and orthotopic in vivo (Project 1) and immunological (Project 2) models. Thesestudies will also employ Core C to test inhibitors on melanoma cells for quality control and for screeningagainst a panel of cell lines. Together with the other projects of the program, our studies will contribute tothe mechanistic understanding of the roles played by the RAS-RAF-MEK-ERK (MAPK) and PI3K-AKTsignaling pathways in melanoma and to the development of novel strategies for the treatment of melanoma.
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