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  • Ze'ev Ronai, Ph.D.

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Details

Project TitleTargeting the E3 ubiquitin ligase Siah in prostate cancer
Track Code10-013/Ronai
Short Description
Abstract
 
TagsSiah, ubiquitination, ups, prostate, cancer, HIF, FoxA2, neuroendocrine
 
Posted DateMar 12, 2012 3:19 PM

Researcher

Name
Ze'ev Ronai, Ph.D.

Manager

Name
Alejandrina Warrick

                                  

Background

The RING finger ubiquitin ligase Siah regulates the stability of its substrates either by direct association, or via an adaptor protein (i.e. PHYL or SIP). Among Siah2 substrates are prolyl hydroxylase 3 (PHD3) which modifies HIF1 to enable its association with- and ubiquitination by- pVHL, resulting in its degradation.  Siah2 also controls the ubiquitination and consequent degradation of TRAF2, following stress and DNA damage. Siah2 effect of both TRAF2 and PHD3 require presence of adaptor proteins. Other substrates Siah2 controls include Sprouty2 (SPRY2), AKAP121 and ASPP1/2 and alpha-keto glutarate dehydrogenase, which do not require presence of adaptor proteins.

Technology

To determine the role of Siah2 in tumor and metastasis researchers have inhibited Siah2 activity by using either a peptide that outcompete binding of adaptor proteins, or RING mutant Siah2, which serves as a dominant negative. Inhibition of Siah2 effectively inhibited tumor development or metastasis, depending on the model tested, in breast, pancreatic, lung, melanoma and prostate cancers. Since inhibition of E3 RING ligases that lack catalytic activities like Siah2, has been a challenge, we have undertaken a structure based design to develop a novel class of inhibitors to this ubiquitin ligase. We have now identified small peptides (~10aa long) that effectively inhibit Siah2 at the low nanomolar range. The approach undertaken makes specific use of structural conformations, which are targeted efficiently and specifically. Those novel class of peptides are evaluated in vitro and in vivo studies, and are expected to provide the foundation for developing new inhibitors for these class of ubiquitin ligases. We expect that the newly identified peptides will also provide the basis for identification of chemical structures that can be used in clinical space.

Application

It is expected that the proposed studies will allow assessment of novel class of inhibitors with therapeutic impact on several types of human cancer. Unlike the available drugs that target overall proteasomes, this approach offers a selective targeting of ubiquitin ligase which is upregulated in human cancer and whose inhibition was shown to attenuate the growth or metastasis of tumors in a number of initial preclinical studies.

Advantages

There is strong ground for targeting Siah ligase in cancer; they are upregulated (expression and activity) and their inhibition effectively block tumor and or metastasis of number of tumor types. Our new technology, based on structure-designed peptides, have provided a proof of concept for our ability to develop a novel class of inhibitors to RING finger E3 ubiquitin ligases. The approach can be used as template for identifying inhibitors to other ligases of the same family. Our identification of potent small peptides that exhibit unprecedented efficiency in selective inhibition of Siah provides the foundation for identification of small molecules that can be further explored in clinical applications.

IP Status

Full Title: Modulation of Siah2 and FoxA2 to Treat Cancers Exhibiting Neuroendocrine Carcinoma Phenotype

U.S. Patent/Application filed

Priority date: 06-04-2010

Contact

Office of Technology Management and Commercialization
Sanford Burnham Prebys Medical Discovery Institute
10901 N. Torrey Pines Road
La Jolla, CA 92037

otmc@sbpdiscovery.org

Development Status

Peptide optimization

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