β-catenin inhibitors in cancer therapeutics: intricacies and way forward

Abstract

β-catenin is an evolutionary conserved, quintessential, multifaceted protein that plays vital roles in cellular homeostasis, embryonic development, organogenesis, stem cell maintenance, cell proliferation, migration, differentiation, apoptosis, and pathogenesis of various human diseases including cancer. β-catenin manifests both signaling and adhesive features. It acts as a pivotal player in intracellular signaling as a component of versatile WNT signaling cascade involved in embryonic development, homeostasis as well as in carcinogenesis. It is also involved in Ca 2+ dependent cell adhesion via interaction with E-cadherin at the adherens junctions. Aberrant β-catenin expression and its nuclear accumulation promote the transcription of various oncogenes including c-Myc and cyclinD1, thereby contributing to tumor initiation, development, and progression. β-catenin’s expression is closely regulated at various levels including its stability, sub-cellular localization, as well as transcriptional activity. Understanding the molecular mechanisms of regulation of β-catenin and its atypical expression will provide researchers not only the novel insights into the pathogenesis and progression of cancer but also will help in deciphering new therapeutic avenues. In the present review, we have summarized the dual functions of β-catenin, its role in signaling, associated mutations as well as its role in carcinogenesis and tumor progression of various cancers. Additionally, we have discussed the challenges associated with targeting β-catenin molecule with the presently available drugs and suggested the possible way forward in designing new therapeutic alternatives against this oncogene.

Discovery of New Anti-Cancer Agents against Patient-Derived Sorafenib-Resistant Papillary Thyroid Cancer

“…We have particularly focused on the results showing that sorafenib-resistant PTC was greatly stimulated by calcium, and cancer stemness involved the following signaling pathways (calcium, Notch, Wnt, PPAR, PI3K/Akt, and TGF/SMAD) than sorafenib-sensitive PTC (Figure 1C, top and bottom) in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis [28][29][30][31][32]. We hypothesized that highly stimulated calcium-related signaling pathways in sorafenib-resistant PTC cells were key players in escaping cytoplasmic calcium mediated apoptosis under severe endoplasmic reticulum (ER) stress conditions via anti-cancer drug-treated conditions [28,29,33,34]. RNA-seq analysis showed that there was a minor distinction between SERCA (ATP2A) isoforms.…”

Modulating β-catenin/BCL9 interaction with cell-membrane-camouflaged carnosic acid to inhibit Wnt pathway and enhance tumor immune response

“…Additionally, this binding exhibits a relatively substantial binding area and a moderate binding capacity, making it inherently advantageous for the development of inhibitors ( 47 ). CA, a small molecule derived from natural substances, was discovered to exhibit binding affinity towards the H1 helix of β-catenin in close proximity to BCL9 binding site, consequently disrupting the stability of β-catenin and facilitating its oligomerization and subsequent degradation ( 31 , 56 ). This compound emerged as a highly promising therapeutic candidate for impeding the interaction between β-catenin and BCL9.…”

Covalent Degrader of the Oncogenic Transcription Factor β-Catenin

“…4,5 However, the mechanism of inhibition of these compounds is poorly understood, and these compounds contain functional groups like quinones or taxoflavins that are concerning substructures associated with pan assay interference compounds (PAINS). 5 ICG-001 disrupts binding between CTNNB1 and CBP through binding with CBP and are not particularly potent with micromolar potency. 6 Tankyrase inhibitors, such as IWR-1 and XAV939, stabilize axin and the CK1 activator pryivinium to enhance the activity of the destruction complex, but these compounds do not directly interact with CTNNB1.…”

“…Many efforts have been made to target the Wnt pathway for cancer therapy. − PKF115-584 and CGP04090 disrupt interactions between CTNNB1 and TCF. , However, the mechanism of inhibition of these compounds is poorly understood, and these compounds contain functional groups like quinones or taxoflavins that are concerning substructures associated with pan assay interference compounds (PAINS) . ICG-001 disrupts binding between CTNNB1 and CBP through binding with CBP and are not particularly potent with micromolar potency .…”