Abstract
Abnormal regulation of β-catenin initiates an oncogenic program that serves as a main driver of many cancers. Albeit challenging, β-catenin is an attractive drug target due to its role in maintenance of cancer stem cells and potential to eliminate cancer relapse. We have identified C2, a novel β-catenin inhibitor, which is a small molecule that binds to a novel allosteric site on the surface of β-catenin. C2 selectively inhibits β-catenin, lowers its cellular load and significantly reduces viability of β-catenin-driven cancer cells. Through direct binding to β-catenin, C2 renders the target inactive that eventually activates proteasome system for its removal. Here we report a novel pharmacologic approach for selective inhibition of β-catenin via targeting a cryptic allosteric modulation site. Our findings may provide a new perspective for therapeutic targeting of β-catenin.
Highlights
Abnormal regulation of β-catenin initiates an oncogenic program that serves as a main driver of many cancers
Increased nuclear presence of β-catenin activates the TCF/LEF1-mediated oncogenic events leading to increased stem cell-like behavior in cancers and poor clinical prognosis[8,9]
Site C spans across armadillo domains 8 through 10, which is functionally isolated from the binding sites of TCF4, AXIN1 and BCL9
Summary
Abnormal regulation of β-catenin initiates an oncogenic program that serves as a main driver of many cancers. Impaired APC function leads to over-expression of β-catenin, which in turn renders cancer cells sensitive to its inhibition[15,16] This vulnerability of many colon cancers is at the core of new therapeutic approaches for β-catenin, and may serve as a source of selectivity for novel β-catenin inhibitors. One recent study reports discovery of inhibitors iCRT-3, -5 and -14 that target the CRT complex[18] While this provides hope for direct targeting of β-catenin, it is not clear whether they trigger degradation of β-catenin, raising concerns about the possibility of its re-localization back into the nucleus. We anticipate that our findings will contribute to the understanding of basic β-catenin biology, as well as encourage further drug discovery
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