Patent Watch

August 4, 2014

Wnt signaling pathway inhibitors are promising cancer therapies. Inventors K. Schiemann, F. Stieber, and C. Esdar disclose substituted azaheterobicyclic compounds that are Wnt pathway inhibitors that may be useful for treating inflammatory or hyperproliferative diseases such as cancer

The Wnt signaling (signal transduction) pathways are consist of proteins that pass signals from outside a cell through cell surface receptors to the inside of the cell. Wnt proteins are a large family of cysteine-rich secreted ligands that bind to a receptor complex of the members of the frizzled protein family. Wnt signaling activates three pathways: the canonical Wnt/β-catenin cascade, the noncanonical planar cell polarity pathway, and the Wnt/Ca2+ pathway.

The canonical pathway is the best understood and the most relevant to cancer. Binding Wnt proteins to the frizzled receptor allows β-catenin, the key mediator of Wnt signaling, to accumulate in the cytoplasm and then translocate into the nucleus. There it regulates target gene expression in combination with members of the DNA-binding T cell factor I lymphoid enhancer factor family.

If Wnt ligands are absent, however, β-catenin is phosphorylated by a protein complex made of axin, adenomatous polyposis coli (APC), glycogen synthase kinase 3β (GSK3β), and casein kinase 1. Phosphorylation marks β-catenin for destruction via ubiquitination and degradation by the proteasome. The binding of Wnt to the frizzled receptor inhibits the axin–APC–GSK3J3 complex and stops the phosphorylation of β-catenin.

Several types of tumors often contain overactivated Wnt/β-catenin signaling cascades. Some proteins of the pathway that are tumor suppressors can mutate and act as oncogenes. For example, the tumor suppressor APC mutates in almost 60% of colon cancers. Many colon cancers express mutated stabilized β-catenin that cannot be phosphorylated. Mutations of the tumor suppressor axin have been detected in hepatocellular, lung, and colon cancers.

Therefore, inhibiting the Wnt/β-catenin signaling pathway is a promising therapeutic target for cancer treatment. Although some Wnt pathway inhibitors have been reported, there is a significant need for more efficient Wnt pathway inhibitors.

The inventors report the structures of 300 examples of general formula 1, including representative compounds 27 (see figure). 

General structure and six examples of Wnt pathway inhibitors

They used the cellular assay for Wnt pathway activity to evaluate the compounds. IC50 values for the compounds ranged from <0.05 to 5.0 μM. (IC50 is the half-maximal inhibitory concentration, or the concentration of an agent needed to reduce the activity of a biological process by 50%.) IC50 data classifications from this assay for the six examples are shown in the table.

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Cellular assay for Wnt
pathway activity IC50 classification
IC50 classifications           
A: IC50 < 0.05 μΜ
B: IC50 = 0.05–0.10 μΜ
C: IC50 = 0.10–0.50 μΜ
D: IC50 = 0.50–1.00 μΜ
E: IC50 = 1.00–5.00 μΜ


(Merck Patent GmbH [Darmstadt, Germany]; Cancer Research Technology Ltd. [London]. WIPO publication WO2014 086453, June 12, 2014; Ahmed F. Abdel-Magid)