Discovery and characterization of a potent Wnt and hedgehog signaling pathways dual inhibitor

Ma, Haikuo; Chen, Qin; Zhu, Fang; Zheng, Jiyue; Li, Jiajun; Zhang, Hongjian; Chen, Shuaishuai; Xing, Haimei; Luo, Liang; Zheng, Long Tai; He, Sudan; Zhang, Xiaohu

doi:10.1016/j.ejmech.2018.02.034

Cited by 8 publications

(6 citation statements)

References 42 publications

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“…Compound 1 did not show significant cytotoxicity up to 20 μM and apparent toxicity in mice at 10 mg. The results provide evidence that compound 1 can be further investigated for Wnt and Hedgehog-addicted cancers in future studies (Ma et al, 2018).…”

Section: F I G U R Ementioning

confidence: 73%

“…In 2016, CGX1321 has entered phase 1/1b clinical trial study (Table 1) to investigate the drug efficacy in advanced solid and gastrointestinal tumors in single-agent and combination-therapy conditions, respectively. Recently, Ma et al (2018) characterized a dual-action inhibitor of Wnt and Hedgehog transduction pathway as compound 1. The results of luciferase activity showed that compound 1 efficiently inhibited both Wnt/β-catenin and Hedgehog signaling pathways with IC50 value of 0.5 and 71 nM, respectively.…”

Section: F I G U R Ementioning

confidence: 99%

“…Recently, Ma et al. (2018) characterized a dual‐action inhibitor of Wnt and Hedgehog transduction pathway as compound 1 . The results of luciferase activity showed that compound 1 efficiently inhibited both Wnt/β‐catenin and Hedgehog signaling pathways with IC50 value of 0.5 and 71 nM, respectively.…”

Section: Porcn Catalytic Activitymentioning

confidence: 99%

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Application of porcupine inhibitors in stem cell fate determination

et al. 2020

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Porcupine (Porcn), a membrane‐bound O‐acyltransferase, is an endoplasmic reticulum‐located protein that has catalytic activity. Porcn is involved in post‐translational lipid modification of wingless‐Int (Wnt) proteins and serves as an indispensable step in the Wnt proper secretion and signaling. Small‐molecule inhibitors targeting Porcn catalytic function in vitro and in vivo are of great interest not only for treating cancer and fibrotic disorders but also in the field of regenerative medicine. Although a number of studies have been conducted, the exact role of Porcn in stem cell fate is not entirely clear. In some cases, Porcn inhibition declined differentiation rate, and in others, it induced stem cell differentiation toward specific lineages. In this review, we first elaborated the Porcn catalytic activity and its inhibitors. Then, we discussed about the recently reported results of Porcn inhibitors in stem cells self‐renewal and differentiation.

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Section: F I G U R Ementioning

confidence: 73%

Section: F I G U R Ementioning

confidence: 99%

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Application of porcupine inhibitors in stem cell fate determination

et al. 2020

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“…Additional studies indicated Porcn as the specific target of this compound for Wnt abolition. Moreover, compound 1 did not exhibit remarkable cytotoxicity and toxicity up to 20 μM and 10 mg in in vitro and in vivo, respectively (Ma et al, 2018). Table 1 summarizes the available Porcn inhibitors in preclinical or clinical stages.…”

Section: Porcn Small Molecule Inhibitorsmentioning

confidence: 99%

Porcn as a novel therapeutic target in cancer therapy: A review

Raeisi

Saberivand

Velaei

et al. 2022

Cell Biology International

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Wingless-related integration site (Wnt) signaling is one of the main oncogenic pathways in different malignancies. Therefore, targeting this pathway has been considered an exciting strategy in cancer treatment. Porcn is among the central enzymes in this pathway that has recently been considered for cancer-targeted therapy. As a membrane-bound O-acyltransferase, Porcn plays a critical role in wnt ligand palmitoylation and its subsequent secretion. In addition to Porcn's role in stem cell signaling and differentiation, recent findings have shown its role in developing and progressing colorectal, pancreatic, liver, head, and neck cancers. Developed small molecule inhibitors have also opened a promising window toward cancer treatment strategies. In this review, the structure and biological role of Porcn in different cancer-related signaling pathways and inhibitors used for inhibiting this enzyme are discussed.

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“…Recently, Ma et al 65 developed a potent molecule 4u (Figure 4E) that inhibited the Wnt and Hh pathway at subnanomolar concentration. The Wnt and Hh signaling pathways interact and coordinate during embryonic development and are implicated in tumorigenesis and metastasis.…”

Section: Recent Advances In Design Of Hh Pathway Inhibitorsmentioning

confidence: 99%

Design of Hedgehog pathway inhibitors for cancer treatment

Bariwal

Kumar

Dong

et al. 2018

Medicinal Research Reviews

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Hedgehog (Hh) signaling is involved in the initiation and progression of various cancers and is essential for embryonic and postnatal development. This pathway remains in the quiescent state in adult tissues but gets activated upon inflammation and injuries. Inhibition of Hh signaling pathway using natural and synthetic compounds has provided an attractive approach for treating cancer and inflammatory diseases. While the majority of Hh pathway inhibitors target the transmembrane protein Smoothened (SMO), some small molecules that target the signaling cascade downstream of SMO are of particular interest. Substantial efforts are being made to develop new molecules targeting various components of the Hh signaling pathway. Here, we have discussed the discovery of small molecules as Hh inhibitors from the diverse chemical background. Also, some of the recently identified natural products have been included as a separate section. Extensive structure-activity relationship (SAR) of each chemical class is the focus of this review. Also, clinically advanced molecules are discussed from the last 5 to 7 years. Nanomedicine-based delivery approaches for Hh pathway inhibitors are also discussed concisely.

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Discovery and characterization of a potent Wnt and hedgehog signaling pathways dual inhibitor

Cited by 8 publications

References 42 publications

Application of porcupine inhibitors in stem cell fate determination

Application of porcupine inhibitors in stem cell fate determination

Porcn as a novel therapeutic target in cancer therapy: A review

Design of Hedgehog pathway inhibitors for cancer treatment

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