AsianScientist (Sep. 5, 2016) – Scientists in Japan have discovered a small molecule that inhibits Wnt signaling, a key pathway in the development of cancer stem cells (CSCs). Details of the NCB-0846 inhibitor are published in the journal Nature Communications.
Colorectal cancer is a major cause of cancer mortality, accounting for approximately 700,000 deaths annually worldwide. Over 90 percent of colorectal cancers carry somatic mutations in Wnt signaling pathway genes, which in turn leads to the generation of CSCs. Previously, a kinase called Traf2- and Nck-interacting kinase (TNIK) was found to regulate Wnt signaling in the most downstream part of the pathway, with a role in the initiation of colorectal cancer stem cells and growth of colorectal cancer cells.
On the basis of these results, a team of researchers from the National Cancer Center Research Institute, the RIKEN Center for Life Science Technologies and Carna Biosciences Inc. in Japan screened an in-house kinase-focused compound library for small molecules that could inhibit TNIK activity. Subsequent lead optimization resulted in the identification of NCB-0846, and X-ray co-crystal structure studies revealed that NCB-0846 binds to TNIK in an inactive conformation, which is likely to be essential for Wnt inhibition.
NCB-0846, which is orally administrable, suppressed the growth of patient-derived colorectal cancer xenografts in mice, and also suppressed various CSC activities of colorectal cancer cells and their expression of CSC markers.
“We’re very encouraged by our promising preclinical data for NCB-0846, especially considering the difficulty in targeting this pathway to date, and shortly we hope to conduct a clinical trial at the NCC hospitals,” said Dr. Tesshi Yamada, chief of the division of chemotherapy and clinical research at the National Cancer Center Research Institute.
NCB-0846 is currently under pre-clinical development, with the aim of Investigational New Drug filing. If successful, it may provide a new therapy option for patients with drug-refractory colorectal cancer.
The article can be found at: Masuda et al. (2016) TNIK Inhibition Abrogates Colorectal Cancer Stemness.
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Source: RIKEN; Photo: Shutterstock.
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