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Emergence of TNIK inhibitors in cancer therapeutics.

ABSTRACT: The outcome of patients with metastatic colorectal cancer remains unsatisfactory. To improve patient prognosis, it will be necessary to identify new drug targets based on molecules that are essential for colorectal carcinogenesis, and to develop therapeutics that target such molecules. The great majority of colorectal cancers (>90%) have mutations in at least one Wnt signaling pathway gene. Aberrant activation of Wnt signaling is a major force driving colorectal carcinogenesis. Several therapeutics targeting Wnt pathway molecules, including porcupine, frizzled receptors and tankyrases, have been developed, but none of them have yet been incorporated into clinical practice. Wnt signaling is most frequently activated by loss of function of the adenomatous polyposis coli (APC) tumor suppressor gene. Restoration of APC gene function does not seem to be a realistic therapeutic approach, and, therefore, only Wnt signaling molecules downstream of the APC gene product can be considered as targets for pharmacological intervention. Traf2 and Nck-interacting protein kinase (TNIK) was identified as a regulatory component of the ?-catenin and T-cell factor-4 (TCF-4) transcriptional complex. Several small-molecule compounds targeting this protein kinase have been shown to have anti-tumor effects against various cancers. An anthelmintic agent, mebendazole, was recently identified as a selective inhibitor of TNIK and is under clinical evaluation. TNIK regulates Wnt signaling in the most downstream part of the pathway, and its pharmacological inhibition seems to be a promising therapeutic approach. We demonstrated the feasibility of this approach by developing a small-molecule TNIK inhibitor, NCB-0846.

SUBMITTER: Yamada T

PROVIDER: S-EPMC5448614 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Emergence of TNIK inhibitors in cancer therapeutics.

Yamada Tesshi T Masuda Mari M

Cancer science 20170424 5

The outcome of patients with metastatic colorectal cancer remains unsatisfactory. To improve patient prognosis, it will be necessary to identify new drug targets based on molecules that are essential for colorectal carcinogenesis, and to develop therapeutics that target such molecules. The great majority of colorectal cancers (>90%) have mutations in at least one Wnt signaling pathway gene. Aberrant activation of Wnt signaling is a major force driving colorectal carcinogenesis. Several therapeut ...[more]

PMID: 28208209

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Project description:Plants are known to have many secondary metabolites and phytochemical compounds which are highly explored at biochemical and molecular genetics level and exploited enormously in the human health care sector. However, there are other less explored small molecular weight proteins, which inhibit proteases/proteinases. Plants are good sources of protease inhibitors (PIs) which protect them against diseases, insects, pests, and herbivores. In the past, proteinaceous PIs were considered primarily as protein-degrading enzymes. Nevertheless, this view has significantly changed and PIs are now treated as very important signaling molecules in many biological activities such as inflammation, apoptosis, blood clotting and hormone processing. In recent years, PIs have been examined extensively as therapeutic agents, primarily to deal with various human cancers. Interestingly, many plant-based PIs are also found to be effective against cardiovascular diseases, osteoporosis, inflammatory diseases and neurological disorders. Several plant PIs are under further evaluation in in vitro clinical trials. Among all types of PIs, Bowman-Birk inhibitors (BBI) have been studied extensively in the treatment of many diseases, especially in the field of cancer prevention. So far, crops such as beans, potatoes, barley, squash, millet, wheat, buckwheat, groundnut, chickpea, pigeonpea, corn, and pineapple have been identified as good sources of PIs. The PI content of such foods has a significant influence on human health disorders, particularly in the regions where people mostly depend on these kind of foods. These natural PIs vary in concentration, protease specificity, heat stability, and sometimes several PIs may be present in the same species or tissue. However, it is important to carry out individual studies to identify the potential effects of each PI on human health. PIs in plants make them incredible sources to determine novel PIs with specific pharmacological and therapeutic effects due to their peculiarity and superabundance.

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Emergence of TNIK inhibitors in cancer therapeutics.

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Emergence of TNIK inhibitors in cancer therapeutics.

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