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KRICT-Yonsei Univ, Small molecule targeting Cancer stem cells "Licensing agreement with FutuRx”

입력 2019-03-14 13:25 수정 2019-03-18 10:38

바이오스펙테이터 Sungmin Kim 기자

TNIK targeted small molecule compound, targets the Wnt signaling which causes colon cancer, and inhibition of cancer stem cells… “Synergistic effect from the mono or combination administration

Domestic researchers discovered ‘first-in-class’ anticancer drug candidate for colon cancer, was successfully transferred to a global incubator. Dr. Lee Hyeok and his team and Professor Shin Sang-jun and his team of Yonsei University announced on the last month that they discovered colon cancer therapeutics candidate and licensed out to the global incubator ‘FutuRx’, with establishment of TNIK Therapeutics. The incubator helps the efficient process of clinical development by introducing candidate materials for new drugs at its initial stage.

FutuRx is a global incubator founded by the biggest investment company specializing in biopharma, OrbiMed, under the support of the Israeli government, with Takeda and J&J, the large global pharma, as partners. The ratio of competition to enter FutuRx reached 90:1. According to the 2017 statistics, 43 % of the new projects of FutuRx came from Israel, whereas 57 % of them are candidate materials for new drug introduced from the United States of America and Europe. BiomX, the microbiome company excavated by FutuRx, and Mitoconix, the company developing mitochondria new drug, invited investment of more than 20 million USD for Series A. This is the first case among domestic companies of the discovery of a candidate material for new drug, and was selected by FutuRx.

The candidate material for anticancer agent, transferred to FutuRx, is the ‘TNIK Inhibitor’, which will be developed as a therapeutic agent for colon cancer. TNIK Inhibitor attains anticancer effect through inhibiting the binding of β-Catenin/TNIK, the sub-factor of WNT signal transfer that causes cancer. In particular, the manifestation of possibilities to suppress cancer stem cell was appraised favorably. In 2018, the research teams filed the applications for 2 domestic patent rights and 2 recent PCTs for the TNIK Inhibition compound.

The share of TNIK Therapeutics will be shared by FutuRx, OrbiMed, Takeda, and J&J with the domestic research teams as the movement of TNIK Therapeutics into FutuRx. TNIK Therapeutics is supposed to receive 2.3 million USD as a research fund for 3 years from FutuRx, according to the milestone. In addition, the know-hows, directions for development, and network will be provided by the advisory committee of big pharma and global fund.

Lee Hyeok, the Director of KRICT, stated the significance of research as follows: “… this accomplishment is the first case of the recognition of the possibilities and excellence of therapeutic agent from a compound developed by spontaneous domestic technology…”. “… the therapeutic agent derived from the compound is expected to treat patients worldwide who are suffering from colon cancer, and improve the quality of life of patients …”.

Professor Shin Sang-jun of Yonsei University anticipated, “… with the material inhibiting TNIK activity, the development of a therapeutic agent for the prevention or treatment of cancer having a synergistic effect, from individual administration, or together with other anticancer agents, could be available…”.

The research was supported by the fund for the Development of Infrastructure for Technologies of Next-Generation in the Projects for Development of Bio-Medical Technologies of the National Research Foundation of Korea, under the Ministry of Science, Technology, Information and Telecommunications.

'Why' TNIK inhibitor for colon cancer

If it is found at an early stage, Colorectal cancer (CRC) exhibits survival rates of 65–90 %, whereas its metastasis is difficult to cure; hence the survival rate after 5 years drops to 11 %. The conventional chemical anticancer agent or immuno-anticancer agent exhibits low drug reactions from patients suffering the metastasis of colorectal cancer.

Recently, the cancer stem cells were reported as having significant effects, causing colon cancer and its metastasis. Cancer stem cells have the characteristics of self-renewal and pluripotency that disturb treatment of the disease. Therefore, the drugs that are capable of suppressing cancer stem cells have been needed.

Among the factors that cause colon cancer, Wnt signal transfer is most spotlighted. The degree of manifestation in the tissues of colon cancer of β-Catenin, the sub-factor, is increased. Thus certified drugs for the inhibition of signal transference are needed, which are yet to be found. The research team targeted the TNIK, which is binding with β-Catenin to inhibit Wnt signal transference that causes colon cancer.

The composite of β-Catenin is created in normal cells if Wnt signal is absent, and in this way the β-Catenin is decomposed. More concretely, the β-Catenin forms the scaffolding protein complex together with APC/Axin/CK1a/GSK-3β; hence the β-Catenin decomposes. Here, the situation changes with the binding of Wnt protein with the receptor on the surface of cells. The Wnt signal prevents the creation of scaffolding protein complex; as a result, the β-Catenin is not decomposed. The β-Catenin combines with TNIK, and transfers to the nucleus. The complex moves into the inside of the nucleus, binds with TCF4 transcription factor, and thereby activates the transcription of genes that promotes cell growth.

However, for cancer cells, the generation of APC mutation disables the formation of scaffolding protein complex. Therefore, the Wnt signal transfer is kept activated, and the β-Catenin binds with TNIK, which activates the transcription of TCF4. As a result, the growth, proliferation, transference, and vasculogenesis for cancer cells are promoted. Thus TNIK inhibitor prevents the transfer of TNIK/β-Catenin complex into the nucleus, which is the last signal transfer process. There is other significance. It has been known that the signal transfer of TNIK that directly interacts with β-Catenin and TCF4 activates the genes that are important for the proliferation of cancer stem cells. By this process, the effects of TNIK inhibitor, which inhibits cancer stem cells transferring colon cancer, can be expected.

The research team has identified the effect of inhibition over the proliferation and survival of cancer cells by the sole administration of TNIK inhibitor into the cell strain of colon cancer, or the joint administration with existing therapeutic agents. The research team also identified the manifestation of TNIK protein reduced at the cell strain of colon cancer by the compound, and the actual inhibition of the formation of β-Catenin/TNIK/TCF4 complex. The inhibition of cancer stem cells of colon cancer was also identified, and the new biomarker capable of identifying the inhibition of the growth of cancer stem cells by TNIK inhibitor was found.

The indications of the inhibitor are expected to be manifested from other carcinomas. The levels of activity of TNIK protein are elevated in carcinomas, such as breast cancer, brain tumors, gastric cancer, and ovarian cancer etc.; in this way, other carcinomas are expected to respond to the anticancer efficacy of TNIK inhibitor.

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