Aberrant Wnt pathway signaling is thought to be important for the growth of triple negative breast cancer stem cells and bulk cancer cells. The β-catenin/BCL9 protein-protein interaction (PPI) is thought to be near the end of the Wnt pathway and is therefore considered to be a good target with minimal side effects. There is also some recent evidence to suggest that activation of the Wnt/β-catenin pathway may help cancer cells avoid a T-cell based anti-tumor immune response. Drug-like and selective β-catenin/BCL9 PPI inhibitors have been developed with an IC50 of at least 0.87 uM. The parent compound has excellent microsomal stability and pharmacokinetic properties with an oral bioavailability (F) of 83%, and triggers rapid apoptosis of cancer cells with hyperactive β-catenin signaling.
- There were estimated to be about 221,270 new cases of breast cancer in 2019. Triple negative breast cancer is found in about 10–20% of breast cancer patients. TNBC is highly metastatic, less responsive to standard treatment, and associated with a high rate of cancer recurrence. Data have indicated dramatic hyperactivation of canonical Wnt signaling in TNBC.
- Compelling basic and clinical studies demonstrate that hyperactivation of β-catenin signaling promotes hallmark characteristics of metastases in several cancers including triple negative breast cancer (TNBC). WNT/β-catenin signaling is also emerging as a key pathway that promotes immune evasion and resistance to immunotherapies.
- The inhibitors of the upstream effectors of the Wnt/β-catenin signaling pathway are less desirable, because those inhibitors have no efficacy for cancer cells harboring more downstream APC and Axin loss-of-function mutations, and β-catenin activation mutations. The upstream inhibitors also disturb noncanonical Wnt signaling pathways.
- BCL9/BCL9L provides the structure for scaffolding the ‘WNT enhanceosome’ and couples β-catenin and Pygos to the T-cell factor (Tcf) and lymphoid enhancer-binding factor (Lef) family of transcriptional factors to transcribe downstream target genes. Many studies have recognized the β-catenin-BCL9-Pygo axis is the key driver of malignancy, facilitating the switch from non-invasive to invasive cancer, provoking cancer progression and metastasis, and promoting immune suppression.
Drug-like β-catenin/BCL9 inhibitor derivatives of a parent compound have been designed and synthesized. AlphaScreen assays indicated that the parent compound disrupted the β-catenin/BCL9 PPI with a Ki of 0.76 ± 0.044 μM and exhibited 220-fold selectivity for disrupting β-catenin/BCL9 over β-catenin/E-cadeherin PPIs. A battery of biochemical and cell-based studies have demonstrated that this parent compound is the first drug-like inhibitor that binds with β-catenin, disrupts the β-catenin-mediated transcriptional complex, selectively inhibits β-catenin signaling activation, regulates Wnt target genes, and triggers rapid apoptosis of cancer cells with hyperactive β-catenin signaling. The parent compound has cell-based IC50s around 10 uM.
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