Discovery of 4-phenyl-2-phenylaminopyridine based TNIK inhibitors

Ho, Koc-Kan; Parnell, K. Mark; Yuan, Yi; Yong, Xu; Kultgen, Steven G.; Hamblin, Steven; Hendrickson, Thomas F.; Luo, Bai; Foulks, Jason M.; McCullar, Michael V.; Kanner, Steven B.

doi:10.1016/j.bmcl.2012.11.013

Cited by 26 publications

(18 citation statements)

References 17 publications

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“…One of these compounds [4-methoxy-3-(2-(3-methoxy-4-morpholinophenylamino)pyridin-4-yl)benzonitrile] (named Compound 9) inhibited the enzyme activity of TNIK with an IC 50 value of 8 nM, but paradoxically had minimal Wnt signal-inhibitory effects (IC 50 >2 μM)28. This paradox might be explainable by a difference in TNIK-binding modes between the reported compounds and ours.…”

Section: Resultsmentioning

confidence: 55%

“…Recently, a series of 4-phenyl-2-phenylaminopyridine-based small-molecule TNIK inhibitors have been reported by other investigators28. One of these compounds [4-methoxy-3-(2-(3-methoxy-4-morpholinophenylamino)pyridin-4-yl)benzonitrile] (named Compound 9) inhibited the enzyme activity of TNIK with an IC 50 value of 8 nM, but paradoxically had minimal Wnt signal-inhibitory effects (IC 50 >2 μM)28.…”

Section: Resultsmentioning

confidence: 99%

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TNIK inhibition abrogates colorectal cancer stemness

Masuda¹,

Uno²,

Ohbayashi³

et al. 2016

Nat Commun

132

158

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Canonical Wnt/β-catenin signalling is essential for maintaining intestinal stem cells, and its constitutive activation has been implicated in colorectal carcinogenesis. We and others have previously identified Traf2- and Nck-interacting kinase (TNIK) as an essential regulatory component of the T-cell factor-4 and β-catenin transcriptional complex. Consistent with this, Tnik-deficient mice are resistant to azoxymethane-induced colon tumorigenesis, and Tnik−/−/Apcmin/+ mutant mice develop significantly fewer intestinal tumours. Here we report the first orally available small-molecule TNIK inhibitor, NCB-0846, having anti-Wnt activity. X-ray co-crystal structure analysis reveals that NCB-0846 binds to TNIK in an inactive conformation, and this binding mode seems to be essential for Wnt inhibition. NCB-0846 suppresses Wnt-driven intestinal tumorigenesis in Apcmin/+ mice and the sphere- and tumour-forming activities of colorectal cancer cells. TNIK is required for the tumour-initiating function of colorectal cancer stem cells. Its inhibition is a promising therapeutic approach.

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Section: Resultsmentioning

confidence: 55%

Section: Resultsmentioning

confidence: 99%

TNIK inhibition abrogates colorectal cancer stemness

Masuda¹,

Uno²,

Ohbayashi³

et al. 2016

Nat Commun

132

158

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“…Further studies for understanding the regulation may bring us new insights for Wnt-independent functions of TNIK. Recently, Ho et al 16 developed a series of potent and selective TNIK inhibitors based on a 4-phenyl-2-phenylaminopyridine scaffold. By using these inhibitors, the authors indicated that pharmacological inhibition of TNIK kinase activity has minimal effects on either Wnt signaling-mediated transcription or viability of the tested colorectal cancer cells.…”

Section: Discussionmentioning

confidence: 99%

The essential role of TNIK gene amplification in gastric cancer growth

Zhang

Wang

et al. 2014

Oncogenesis

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Traf2- and Nck-interacting kinase (TNIK) is one of the germinal center kinase family members involved in cytoskeleton organization and neuronal dendrite extension. Emerging evidence supports that TNIK is essential for activation of WNT signaling pathway in colon cancer growth. To search for novel genetic aberrations that drive carcinogenesis, we performed microarray-based comparative hybridization assay for gene copy number variations in primary tumor samples. Our data showed that TNIK gene was amplified in 7% (8/106) of Chinese gastric cancer patients. Theses amplifications were confirmed by fluorescence in situ hybridization analysis. PAMC82 human gastric cancer and T47D human breast cancer cell lines with TNIK amplification were identified to further understand the function of TNIK gene amplification. RNA-interference-mediated silencing of TNIK resulted in significant inhibition of cell growth and induction of cell death in TNIK-amplified, but not in TNIK-non-amplified, cell lines tested. This selective sensitivity to the TNIK inhibition was also observed under the effect of a small-molecule TNIK inhibitor. Furthermore, our data indicated that TNIK's role in gastric cancer growth was not dependent on Wnt signaling but rather was involved in AKT activation and cell autophagy. Together, our results suggest that TNIK is a novel therapeutic target in gastric cancer and TNIK amplification can be potentially used for patient selection.

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“…A series of 4-phenyl-2-phenylaminopyridine analogs with potent activity against TNIK have been reported by Astex Phamaceutical, Inc. (Salt Lake City, UT) [63]. Compound 1 (IC 50 = 65 nM) was identified from high-throughput screening (HTS) against an in-house kinase-focused compound library (1, (Figure 5)).…”

Section: Phenylaminopyridine-based Tnik Inhibitorsmentioning

confidence: 99%

Targeting the Wnt signaling pathway in colorectal cancer

Sawa¹,

Masuda²,

Yamada³

2015

Expert Opinion on Therapeutic Targets

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APC is a tumor suppressor, and therefore only downstream signal transducers of the APC protein can be considered as targets for pharmaceutical intervention. TRAF2 and NCK-interacting protein kinase (TNIK) was identified as the most downstream regulator of Wnt signaling by two independent research groups, and several classes of small-molecule inhibitors targeting this protein kinase have been developed. TNIK is a multifunctional protein with actions that extend beyond Wnt signaling regulation. Such TNIK inhibitors are expected to have a large variety of clinical applications.

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Discovery of 4-phenyl-2-phenylaminopyridine based TNIK inhibitors

Cited by 26 publications

References 17 publications

TNIK inhibition abrogates colorectal cancer stemness

TNIK inhibition abrogates colorectal cancer stemness

The essential role of TNIK gene amplification in gastric cancer growth

Targeting the Wnt signaling pathway in colorectal cancer

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