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KDDF-201202-01 Development of anticancer drug candidates targeting a new oncoprotein(Oncology, Chemical) [01.04.2013]

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Development and Market Objectives

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 We demonstrated that E2-EPF ubiquitin carrier protein (UCP) induces ubiquitin-mediated proteolysis of the VHL (von Hippel-Lindau) tumor suppressor, resulting in stabilization of hypoxia inducible factor (HIF)-1α and HIF-2α proteins, and thereby promotes proliferation and metastasis of cancer cells (Nat Med 2006). In this stage of research, we aim to develop a non-clinical candidate selectively targeting UCP, which exerts excellent anticancer and pharmacodynamics activities.

 

Unmet Medical Need & Target Patients

○ Since cancer cells grow rapidly and survive robustly compared to normal cells, carcinogenic factors or pathways that are crucially responsible for the growth and survival of cancer cells are usually the target for development of anticancer drugs. The carcinogenic factors are highly expressed and/or activated in cancer cells. E2-EPF UCP has been shown to be highly expressed in most human cancers, such as liver, lung, breast, colorectal, ovarian, and esophageal cancers (PNAS 98, 1176-1181, 2001; Oncogene 23, 6621-6629, 2004; MBC 13, 1977-2000, 2002; Curr Opinion Genet & Develop 17, 71-77, 2007; J Mol Med 87, 307-320, 2009). We also discovered that UCP is highly and frequently expressed in human liver cancer tissues compared to normal tissues, and is often co-expressed with HIF-1α protein. Furthermore, we have observed the occurrence of liver cancer in the transgenic mouse expressing UCP. These results indicate that UCP, as a carcinogenic factor, is directly involved in initiating and progressing liver cancer. Thus, an anticancer agent targeting UCP is potentially applied to the treatment of a variety of primary and metastatic cancers, including liver cancer.

○ Bayer/Onyx pharma's Nexavar, a multiple kinase inhibitor, is the only targeted anticancer drug for the treatment of liver cancer. BMS's Brivanib and Abbott's Linifanib, which are also multiple kinase inhibitors, did not show so strong anticancer activity as Nexavar in a phase 3 clinical trial. In 2010, Pfizer stopped a phase 3 clinical trial with Sunitinib for liver cancer treatment due to its serious side effect compared to Nexavar. Novartis is conducting a phase 3 clinical trial with mTOR inhibitor, Afinitor (everolimus) aiming at liver cancer patients who show no response to Nexavar or develop resistance to it. Lilly is also running a phase 3 clinical trial with ramucirumab, a monoclonal antibody to VEGFR-2, aiming at liver cancer patients who failed in treatment with Nexavar. A phase 2 clinical trial with ArQule's c-Met tyrosine kinase inhibitor showed efficacy in certain liver cancer patient group.

○ As above, the 2nd treatment modality has been developed for liver cancer patients who do not respond to the Nexavar. Also anticancer agents that show therapeutic effect in certain liver patient group are in a clinical trial. However, the failure to develop the kinase inhibitors for liver cancer therapy, such as Brivanib, Linifanib, and Sunitinib, shows the limitation of kinase inhibitor as a liver cancer therapeutic. Although it has been officially approved for liver cancer treatment, Nexabar only improves the survival period of liver cancer patients by an average of just more than 3 months. Liver cancer is one of the most prevalent human cancers worldwide, with 600,000 estimated new cases annually and many deaths. Accordingly, the unmet medical need for a novel liver cancer therapeutic is still high. It is urgently required to develop tailored therapy based on novel targets associated with hepatocellular carcinogenesis. The development of an anticancer drug targeting UCP is expected to meet medical needs in the near future. 
 

Status

We identified a small molecule that inhibits UCP-mediated in vitro ubiquitination of VHL with an IC50 value of ~180 nM and inhibits tumor cell proliferation with GI50 values of 150 nM to 870 nM dependent on cell lines. This chemical intravenously dosed at 5 mg/kg inhibits tumor growth by >70% in mouse xenograft models. The chemical increases the level of VHL and decreases the level of HIFa subunits in cells, but does not greatly affect the levels of MDM2 and p53, suggesting that it preferentially targets the UCP in cells. The PK profile of this chemical needs to be improved.
This chemical serves as a lead compound and is currently being optimized.

Intellectual Property

The patent related to the interaction of UCP with VHL, which can be exploited for cancer therapy, is registered in both Korea (Registered number: 10-877824) and Japan (Registered number: 4972096) and is pending in USA and EU. 

 

Competitive Advantages

Firstly, UCP serves as a novel target for personalized cancer therapy, which leads to development of a First-in-class drug. Secondly, there has been no anticancer agent targeting the VHL-HIF pathway on the market. Third, since UCP is highly expressed in various human cancer cells, an anticancer agent selectively targeting UCP can be applied to various human cancer types including liver cancer and become a blockbuster.
 

Indication

anticancer

Research Period

Jun. 01, 2012~Feb. 28, 2015

Company

Korea research institute of bioscience & biotechnology

Developmental Stage

drug candidate

Additional Information

Contact Information

Contact
Address Company Name: Korea Research Institute of Bioscience and Biotech
WebSite Homepage: http://www.kribb.re.kr/ Contact Person: Dr Dong-Soo Im, Dr Cho-Rok Jung
E-mail: imdongsu@kribb.re.kr Contact: +82-42-860-4172,+82-42-860-4177

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