Review article
Recent advances of β-catenin small molecule inhibitors for cancer therapy: Current development and future perspectives

https://doi.org/10.1016/j.ejmech.2022.114789Get rights and content

Highlights

  • Introduce the mechanism of Wnt/β-catenin signaling pathway and its relationship with cancer.

  • Focusing on the β-catenin inhibitors from the aspects of activity, selectivity, and structure-activity relationship.

  • Discuss the development prospects and future directions of β-catenin inhibitors.

Abstract

The Wnt/β-catenin signaling pathway is involved in many cellular physiological processes, including embryonic development, cell proliferation and differentiation, tissue homeostasis and regeneration, etc. Aberrant activation of Wnt/β-catenin signaling is one of the most typical features in the development and progression of cancer. Abnormal accumulation of β-catenin, a core component of the Wnt/β-catenin signaling pathway, is one of the main factors leading to abnormal activation of the Wnt/β-catenin signaling pathway. Therefore, β-catenin has become an important target for the development of anticancer drugs. Some β-catenin small molecule inhibitors have been shown to have the potential to treat cancer, such as the specific β-catenin/CBP antagonist PRI-724, which has entered phase I/II clinical trials. However, the development and application of β-catenin inhibitors are still challenging due to their selectivity, specificity and physicochemical properties, etc. This review introduces the Wnt/β-catenin signaling pathway, focuses on the research progress of β-catenin small molecule inhibitors, and prospects for the development of drug in the future.

Introduction

The Wnt/β-catenin signaling pathway is a conserved signaling axis that plays an important role in embryonic development, cell differentiation, cell renewal, tissue homeostasis and tissue regeneration, and is regulated by a variety of extracellular, cytoplasmic and nuclear regulatory factors [1]. Mutations in components of the Wnt/β-catenin signaling pathway usually lead to aberrant activation of this pathway, resulting in the overexpression of target genes (such as c-myc and cyclin D1) regulated by this pathway related to cell proliferation, growth and apoptosis, and promote cancers invasion and metastasis [2]. β-catenin is located downstream of the Wnt/β-catenin signaling pathway and can serve as a connection between cytoplasm and nucleus. The expression of target genes is activated when β-catenin interacts with transcription factors T-cell factor/lymphoid enhancer factor (TCF/LEF) family, transcription coactivator B-cell lymphoma 9 (BCL9) or transcription cAMP-response element binding protein (CREB)-binding protein (CBP)/p300, etc. [3]. The mutations in upstream components of this pathway, such as Wnt ligand, scaffolding protein Axin and adenomatous polyposis coli (APC), usually leads to abnormal accumulation of β-catenin due to the unique location of β-catenin in the Wnt/β-catenin signaling pathway, thereby resulting in the dysregulation of the pathway. Therefore, inhibitors that directly target β-catenin could cut off the aberrant activation of the Wnt/β-catenin signaling pathway caused by upstream signal mutations, which is crucial for the treatment of cancers associated with this pathway [4].

Over the years, many researchers have discovered and designed several β-catenin small molecule inhibitors by different methods and demonstrated their antitumor activity in vitro and in vivo, such as the β-catenin/TCF4 protein-protein interaction (PPI) inhibitor UU-T01 (40) [5] and β-catenin/BCL9 PPI inhibitor ZW4864 (59) [6]. In addition, several inhibitors have entered clinical studies. For example, PRI-724 (61), a second-generation specific β-catenin/CBP antagonist developed by Prism Pharma, can inhibit the proliferation of cancer cells. It has been shown to be safe in preclinical studies and has entered phase I/II clinical trials (NCT01764477, NCT01302405, NCT01606579 and NCT02413853) [[7], [8], [9], [10], [11]]. However, there are some limitations in the β-catenin small molecule inhibitors, such as lack of selectivity, poor physicochemical properties, cytotoxicity and so on [[12], [13], [14]]. Therefore, none of the β-catenin small molecule inhibitors have been approved for clinical treatment of cancer currently.

To further develop β-catenin small molecule inhibitors with anticancer potential, it is necessary to understand the Wnt/β-catenin signaling pathway and existing β-catenin small molecule inhibitors. Here, the review introduces the Wnt/β-catenin signaling pathway, reviews the research progress of β-catenin small molecule inhibitors in recent years, summarizes the development of the inhibitors, evaluates their biological characteristics, and discusses their structure-activity relationship (SAR), in order to provide guidance for further development of drug.

Section snippets

The structure of β-catenin

β-catenin, as a core component of the Wnt/β-catenin signaling pathway, was first discovered in the conjugate of E-cadherin [15]. β-catenin, encoded by CTNNB1, is a protein in the armadillo family that interacts with its partners and thus plays a central role in the Wnt/β-catenin signaling pathway [16,17]. β-catenin consists of 781 amino acids, including N-terminal domain (∼150 aa), armadillo repeat domain (ARD) composed of 12 armadillo repeats (residues 138–664), and C-terminal domain (∼100 aa)

Development history and current situation of inhibitors

Since the role of Wnt/β-catenin signaling pathway in cancer and the important status of β-catenin in this pathway have been confirmed, many researchers have devoted themselves to developing inhibitors targeting β-catenin to study its anticancer potential. A number of strategies have been identified to indirectly target β-catenin, mainly therapeutic agents targeting upstream effectors of the Wnt/β-catenin signaling pathway. For example, Porcupine inhibitor IWP-2 (1) blocks Wnt signaling by

Challenges in developing β-catenin small molecule inhibitors

β-catenin is considered as a promising target for the treatment of cancer. However, only a few small molecule inhibitors of β-catenin have entered clinical research. Due to the high affinity of β-catenin and other proteins PPIs, large interaction surface, and highly overlapping binding surface, the development of potent and selective inhibitors is a difficult problem to solve [76]. PAINS often display unspecific chemical reactivity and adverse physico-chemical properties. Although they are

Conclusion

The abnormally activated Wnt/β-catenin signaling pathway plays an important role in the development of cancer and the self-renewal and differentiation of CSCs. As a key hub of this pathway, β-catenin level directly affects the transcription of key genes in this pathway, thus regulating cell proliferation, differentiation, apoptosis and other life activities. Small molecule inhibitors targeting β-catenin can inhibit abnormal activation of Wnt/β-catenin signaling pathway, which is a class of

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (Grant 22177083), West China Nursing Discipline Development Special Fund Project, Sichuan University (Grant HXHL21011), and Sichuan Science and Technology Program (Grant 2022NSFSC1290), and the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (Grant 2020-JKCS-014).

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    Panpan Yang, Yumeng Zhu, and Qinwen Zheng contributed equally to this work.

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