While 80% of melanomas harbor mutation in genes that activate the MEK-MAPK signaling pathway, over 50% of melanomas also exhibit upregulation of the AKT/PI3K signaling cascade. Given that inhibitors to components of the MEK/MAPK signaling cascade are not sufficient enough to halt melanoma progression, it is now recognized that combination therapy in melanoma is inevitable. More and more studies provide sound support for the notion that PI3K/Akt is likely to serve as the excellent candidate for combined therapy. Among mechanisms underlying PI3K/Akt contribution to melanoma development is its effect on hypoxia and tumor microenvironment, although underlying mechanisms are not well understood. Among Pten/Akt effectors that play important role in the regulation of HIFIa availability is the ubiquitin ligase Siah2, which is transcriptionally upregulated by Akt. Correspondingly, increased expression of Siah2 is found in malignant melanoma. Further, inhibition of Siah2 effectively blocks melanoma growth and progression. These finding provide the rationale to develop inhibitors to Akt and Siah2 as select targets for treatment of this tumor type. Thus, we propose to use a combination of chemical library screening, structure-based design and medicinal chemistry approaches to obtain potent and selective inhibitors of Akt and Siah. In close collaboration with Project 1 and Core B and C the compounds will be tested in vitro, in 3D cell cultures and in in vivo efficacy and toxicity studies. Overall, our main objective is to develop novel safe and effective agents that by targeting specific genes such as Akt and Siah, which would provide compelling alternative strategies for the treatment of melanoma.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-O)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Sanford-Burnham Medical Research Institute
La Jolla
United States
Zip Code
Maruyama, Takeshi; Araki, Toshihiro; Kawarazaki, Yosuke et al. (2014) Roquin-2 promotes ubiquitin-mediated degradation of ASK1 to regulate stress responses. Sci Signal 7:ra8
Kim, H; Claps, G; Moller, A et al. (2014) Siah2 regulates tight junction integrity and cell polarity through control of ASPP2 stability. Oncogene 33:2004-10
Scortegagna, Marzia; Kim, Hyungsoo; Li, Jian-Liang et al. (2014) Fine tuning of the UPR by the ubiquitin ligases Siah1/2. PLoS Genet 10:e1004348
Qi, Jianfei; Kim, Hyungsoo; Scortegagna, Marzia et al. (2013) Regulators and effectors of Siah ubiquitin ligases. Cell Biochem Biophys 67:15-24
Feng, Yongmei; Lau, Eric; Scortegagna, Marzia et al. (2013) Inhibition of melanoma development in the Nras((Q61K)) ::Ink4a(-/-) mouse model by the small molecule BI-69A11. Pigment Cell Melanoma Res 26:136-42
Barile, Elisa; De, Surya K; Feng, Yongmei et al. (2013) Synthesis and SAR studies of dual AKT/NF-*B inhibitors against melanoma. Chem Biol Drug Des 82:520-33
Stebbins, John L; Santelli, Eugenio; Feng, Yongmei et al. (2013) Structure-based design of covalent Siah inhibitors. Chem Biol 20:973-82
Filipp, Fabian V; Scott, David A; Ronai, Ze'ev A et al. (2012) Reverse TCA cycle flux through isocitrate dehydrogenases 1 and 2 is required for lipogenesis in hypoxic melanoma cells. Pigment Cell Melanoma Res 25:375-83
Feng, Yongmei; Barile, Elisa; De, Surya K et al. (2011) Effective inhibition of melanoma by BI-69A11 is mediated by dual targeting of the AKT and NF-*B pathways. Pigment Cell Melanoma Res 24:703-13
Scott, David A; Richardson, Adam D; Filipp, Fabian V et al. (2011) Comparative metabolic flux profiling of melanoma cell lines: beyond the Warburg effect. J Biol Chem 286:42626-34

Showing the most recent 10 out of 18 publications