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Journal ArticleDOI: 10.1016/J.PHRS.2021.105532

Porcupine inhibitors: Novel and emerging anti-cancer therapeutics targeting the Wnt signaling pathway

04 Mar 2021-Pharmacological Research (Academic Press)-Vol. 167, pp 105532-105532
Abstract: Porcupine is a constituent of the 19 membered Wnt family with diverse biological features such as cell differentiation, cell proliferation, cell migration, apoptosis, etc. Porcupine is a membrane-bound o-acyltransferase family protein that modulates Wnt protein through palmitoylation to allow it to depart the secretory pathway and activate cellular responses. Inhibition of Porcupine prevents palmitoylation of Wnt ligands which in turn blocks the transport of Wnt to the extracellular membrane, thus prevents the immoderate production of β-catenin which helps to control the aberrant cell growth. Clinically, Porcupine inhibitors have shown their potential in treating majorly colorectal cancer, pancreatic cancer, hepatocellular carcinoma, head and neck cancer etc. Till date, none of the Porcupine inhibitors have been in the market and only four molecules, LGK974, ETC159, CGX1321 and RXC004 have reached the Phase I clinical trial. Present review gives a comprehensive insight on Porcupine as a novel drug target for the treatment of cancer as well as recent update on many novel heterocyclic Porcupine inhibitors with their chemical structures and pharmacology. Their physico chemical properties were also predicted using SwissADME server. Major concerns during their development have also been summarised which may throw some light for the future development of novel Porcupine inhibitors for the treatment of cancer.

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Topics: Wnt signaling pathway (56%), Palmitoylation (51%)
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Journal ArticleDOI: 10.1021/ACS.JMEDCHEM.0C01799
Liu Zhiqing1, Pingyuan Wang2, Eric A. Wold2, Qiaoling Song1  +3 moreInstitutions (2)
Abstract: Canonical WNT signaling is an important developmental pathway that has attracted increased attention for anticancer drug discovery From the production and secretion of WNT ligands, their binding to membrane receptors, and the β-catenin destruction complex to the expansive β-catenin transcriptional complex, multiple components have been investigated as drug targets to modulate WNT signaling Significant progress in developing WNT inhibitors such as porcupine inhibitors, tankyrase inhibitors, β-catenin/coactivators, protein-protein interaction inhibitors, casein kinase modulators, DVL inhibitors, and dCTPP1 inhibitors has been made, with several candidates (eg, LGK-974, PRI-724, and ETC-159) in human clinical trials Herein we summarize recent progress in the drug discovery and development of small-molecule inhibitors targeting the canonical WNT pathway, focusing on their specific target proteins, in vitro and in vivo activities, physicochemical properties, and therapeutic potential The relevant opportunities and challenges toward maintaining the balance between efficacy and toxicity in effectively targeting this pathway are also highlighted

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Topics: Wnt signaling pathway (62%), Casein kinase 1 (52%), Drug discovery (52%)

2 Citations


Journal ArticleDOI: 10.1016/J.DRUDIS.2021.07.007
Abstract: WNT/β-catenin signaling orchestrates various physiological processes, including embryonic development, growth, tissue homeostasis, and regeneration. Abnormal WNT/β-catenin signaling is associated with various cancers and its inhibition has shown effective antitumor responses. In this review, we discuss the pathway, potential targets for the development of WNT/β-catenin inhibitors, available inhibitors, and their specific molecular interactions with the target proteins. We also discuss inhibitors that are in clinical trials and describe potential new avenues for therapeutically targeting the WNT/β-catenin pathway. Furthermore, we introduce emerging strategies, including artificial intelligence (AI)-assisted tools and technology-based actionable approaches, to translate WNT/β-catenin inhibitors to the clinic for cancer therapy.

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1 Citations


Open accessPosted ContentDOI: 10.1101/2021.07.19.452875
Jia Yu1, Pei-Ju Liao1, Weijun Xu, Julie R. Jones  +5 moreInstitutions (2)
21 Jul 2021-bioRxiv
Abstract: Wnt signaling is essential for normal development and is a therapeutic target in cancer. The enzyme PORCN, or porcupine, is a membrane-bound O-acyltransferase (MBOAT) that is required for the post-translational modification of all Wnts, adding an essential mono-unsaturated palmitoleic acid to a serine on the tip of Wnt hairpin 2. Inherited mutations in PORCN cause focal dermal hypoplasia, and therapeutic inhibition of PORCN slows the growth of Wnt-dependent cancers. Here, based on homology to mammalian MBOAT proteins we develop and validate a molecular structural model of PORCN. The model accommodates palmitoleoyl-CoA and Wnt hairpin 2 in two tunnels in the conserved catalytic core, shedding light on the catalytic mechanism. The model predicts how previously uncharacterized human variants of uncertain significance can alter PORCN function. Drugs including ETC-159, IWP-L6 and LGK-974 dock in the PORCN catalytic site, providing insights into PORCN pharmacologic inhibition. This structural model provides mechanistic insights into PORCN substrate recognition and catalysis as well as the inhibition of its enzymatic activity and can facilitate the development of improved inhibitors and the understanding of disease relevant PORCN mutants.

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Topics: PORCN (82%)

1 Citations


Book ChapterDOI: 10.1007/164_2021_533
Jin Wang1, Di Feng1, Bo Gao1Institutions (1)
Abstract: Since the discovery of the proto-oncogene Wnt1 (Int1) in 1982, WNT signaling has been identified as one of the most important pathways that regulates a wide range of fundamental developmental and physiological processes in multicellular organisms. The canonical WNT signaling pathway depends on the stabilization and translocation of β-catenin and plays important roles in development and homeostasis. The WNT/planar cell polarity (WNT/PCP) signaling, also known as one of the β-catenin-independent WNT pathways, conveys directional information to coordinate polarized cell behaviors. Similar to WNT/β-catenin signaling, disruption or aberrant activation of WNT/PCP signaling also underlies a variety of developmental defects and cancers. However, the pharmacological targeting of WNT/PCP signaling for therapeutic purposes remains largely unexplored. In this review, we briefly discuss WNT/PCP signaling in development and disease and summarize the known drugs/inhibitors targeting this pathway.

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Topics: Wnt signaling pathway (66%)

1 Citations


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140 results found


Journal ArticleDOI: 10.1016/0092-8674(81)90021-0
09 Aug 1991-Cell
Abstract: DNA from 61 unrelated patients with adenomatous polyposis coli (APC) was examined for mutations in three genes (DP1, SRP19, and DP2.5) located within a 100 kb region deleted in two of the patients. The intron-exon boundary sequences were defined for each of these genes, and single-strand conformation polymorphism analysis of exons from DP2.5 identified four mutations specific to APC patients. Each of two aberrant alleles contained a base substitution changing an amino acid to a stop codon in the predicted peptide; the other mutations were small deletions leading to frameshifts. Analysis of DNA from parents of one of these patients showed that his 2 bp deletion is a new mutation; furthermore, the mutation was transmitted to two of his children. These data have established that DP2.5 is the APC gene.

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2,710 Citations


Open accessJournal ArticleDOI: 10.1038/SREP42717
03 Mar 2017-Scientific Reports
Abstract: To be effective as a drug, a potent molecule must reach its target in the body in sufficient concentration, and stay there in a bioactive form long enough for the expected biologic events to occur. Drug development involves assessment of absorption, distribution, metabolism and excretion (ADME) increasingly earlier in the discovery process, at a stage when considered compounds are numerous but access to the physical samples is limited. In that context, computer models constitute valid alternatives to experiments. Here, we present the new SwissADME web tool that gives free access to a pool of fast yet robust predictive models for physicochemical properties, pharmacokinetics, drug-likeness and medicinal chemistry friendliness, among which in-house proficient methods such as the BOILED-Egg, iLOGP and Bioavailability Radar. Easy efficient input and interpretation are ensured thanks to a user-friendly interface through the login-free website http://www.swissadme.ch. Specialists, but also nonexpert in cheminformatics or computational chemistry can predict rapidly key parameters for a collection of molecules to support their drug discovery endeavours.

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Topics: Cheminformatics (55%), Drug development (54%)

2,561 Citations


Journal ArticleDOI: 10.1126/SCIENCE.1651562
Kenneth W. Kinzler1, Mef Nilbert2, Li Kuo Su2, Bert Vogelstein1  +17 moreInstitutions (6)
09 Aug 1991-Science
Abstract: Recent studies suggest that one or more genes on chromosome 5q21 are important for the development of colorectal cancers, particularly those associated with familial adenomatous polyposis (FAP). To facilitate the identification of genes from this locus, a portion of the region that is tightly linked to FAP was cloned. Six contiguous stretches of sequence (contigs) containing approximately 5.5 Mb of DNA were isolated. Subclones from these contigs were used to identify and position six genes, all of which were expressed in normal colonic mucosa. Two of these genes (APC and MCC) are likely to contribute to colorectal tumorigenesis. The MCC gene had previously been identified by virtue of its mutation in human colorectal tumors. The APC gene was identified in a contig initiated from the MCC gene and was found to encode an unusually large protein. These two closely spaced genes encode proteins predicted to contain coiled-coil regions. Both genes were also expressed in a wide variety of tissues. Further studies of MCC and APC and their potential interaction should prove useful for understanding colorectal neoplasia.

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Topics: Familial adenomatous polyposis (58%), Locus (genetics) (57%), Adenomatous polyposis coli (56%) ... show more

2,313 Citations


Open accessJournal ArticleDOI: 10.1016/J.CELL.2017.05.016
Roel Nusse1, Hans Clevers2Institutions (2)
01 Jun 2017-Cell
Abstract: The WNT signal transduction cascade is a main regulator of development throughout the animal kingdom. Wnts are also key drivers of most types of tissue stem cells in adult mammals. Unsurprisingly, mutated Wnt pathway components are causative to multiple growth-related pathologies and to cancer. Here, we describe the core Wnt/β-catenin signaling pathway, how it controls stem cells, and contributes to disease. Finally, we discuss strategies for Wnt-based therapies.

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Topics: Wnt signaling pathway (66%), Stem cell (52%)

1,735 Citations


Open accessJournal ArticleDOI: 10.1038/NCHEMBIO.137
Baozhi Chen1, Michael E. Dodge2, Wei Tang2, Jianming Lu1  +10 moreInstitutions (2)
Abstract: The pervasive influence of secreted Wnt signaling proteins in tissue homeostasis and tumorigenesis has galvanized efforts to identify small molecules that target Wnt-mediated cellular responses. By screening a diverse synthetic chemical library, we have discovered two new classes of small molecules that disrupt Wnt pathway responses; whereas one class inhibits the activity of Porcupine, a membrane-bound acyltransferase that is essential to the production of Wnt proteins, the other abrogates destruction of Axin proteins, which are suppressors of Wnt/beta-catenin pathway activity. With these small molecules, we establish a chemical genetic approach for studying Wnt pathway responses and stem cell function in adult tissue. We achieve transient, reversible suppression of Wnt/beta-catenin pathway response in vivo, and we establish a mechanism-based approach to target cancerous cell growth. The signal transduction mechanisms shown here to be chemically tractable additionally contribute to Wnt-independent signal transduction pathways and thus could be broadly exploited for chemical genetics and therapeutic goals.

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Topics: LRP6 (68%), Wnt signaling pathway (68%), LRP5 (64%) ... show more

1,259 Citations


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