Discovery and Optimization of a Porcupine Inhibitor

Duraiswamy, Athisayamani Jeyaraj; Lee, May Ann; Madan, Babita; Ang, Shi Hua; Tan, Eldwin Sum Wai; Cheong, Wei Wen; Zhao, Ke; Pendharkar, Vishal; Ding, Li; Chew, Yun Shan; Manoharan, Vithya; Sangthongpitag, Kanda; Alam, Jenefer; Poulsen, Anders; Ho, Soo Yei; Virshup, David M.; Keller, Thomas H.

doi:10.1021/acs.jmedchem.5b00507

Cited by 37 publications

(35 citation statements)

References 22 publications

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“…We were encouraged that our hypothesis was validated by two very recently published papers, albeit the same conclusion was drawn based on a high throughput screen hit followed by an optimization campaign (Figure 1). 10,11 7 and the IC 50 (0.57 nM, Table 2) matched well with the number (0.38 nM) reported in the literature. 5,12 LGK974 was used as a control in all of our assays.…”

Section: Designsupporting

confidence: 88%

“…Again, these results were consistent with the recently published series of compounds that displayed parallel SAR of the linker. 11 Although compound 62 was a racemic mixture of a pair of enantiomers, based on the pharmacophoric model 10 and the molecular similarity of the two series of compounds; we speculate that the S-isomer would be more active.…”

Section: Designmentioning

confidence: 92%

“…A similar trend was observed in a recently published paper, but the clearance of those compounds were moderate to low. 11 Compounds 15, 54, 58, 60 and 62 were then subjected to the standard CYP inhibition test, and they showed weak or no CYP inhibition at concentration of 10 μM ( Table 3). c HLM = human liver microsomes.…”

Section: Wnt3amentioning

confidence: 99%

“…[4][5][6] The breakthrough was made by Novartis in 2012 when LGK974, a potent porcupine inhibitor (Figure 1), was advanced into a phase I clinical trial. 9 Furthermore, recent research activities including the publications of a pharmacophoric model 10 and a lead optimization campaign 11 greatly enhanced the knowledge of porcupine antagonist field; underscore the heightened interests in pursuit of potent Wnt signaling pathway inhibitors (Figure 1). …”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Exploration of the linkage elements of porcupine antagonists led to potent Wnt signaling pathway inhibitors

Dong

et al. 2015

Bioorganic & Medicinal Chemistry

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Section: Designsupporting

confidence: 88%

Section: Designmentioning

confidence: 92%

Section: Wnt3amentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Exploration of the linkage elements of porcupine antagonists led to potent Wnt signaling pathway inhibitors

Dong

et al. 2015

Bioorganic & Medicinal Chemistry

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“…Certain cancer cells exhibit enhanced Wnt production (Voloshanenko et al, 2013). Small molecules that target Wnt secretion in advanced solid tumors show promising inhibitory effects (Duraiswamy et al, 2015;Liu et al, 2013;Madan et al, 2016), and multiple clinical trials (NLM numbers NCT01351103, NCT02278133 and NCT02521844) are ongoing to determine the efficacy and toxicity of these Wnt secretory inhibitors. Thus, it is imperative to gain a better understanding of the molecular basis of Wnt secretion.…”

Section: Introductionmentioning

confidence: 99%

A Wntless–SEC12 complex on the ER membrane regulates early Wnt secretory vesicle assembly and mature ligand export

Sun

Zhang

et al. 2017

Journal of Cell Science

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Wntless (Wls) transports Wnt molecules for secretion; however, the cellular mechanism underlying the initial assembly of Wnt secretory vesicles is still not fully defined. Here, we performed proteomic and mutagenic analyses of mammalian Wls, and report a mechanism for formation of early Wnt secretory vesicles on ER membrane. Wls forms a complex with SEC12 (also known as PREB), an ER membrane-localized guanine nucleotide-exchange factor (GEF) activator of the SAR1 (the SAR1A isoform) small GTPase. Compared to palmitoylation-deficient Wnt molecules, binding of mature Wnt to Wls increases Wls-SEC12 interaction and promotes association of Wls with SAR1, the key activator of the COPII machinery. Incorporation of Wls into this exporting ER compartment is affected by Wnt ligand binding and SEC12 binding to Wls, as well as the structural integrity and, potentially, the folding of the cytosolic tail of Wls. In contrast, Wls-SEC12 binding is stable, with the interacting interface biochemically mapped to cytosolic segments of individual proteins. Mutant Wls that fails to communicate with the COPII machinery cannot effectively support Wnt secretion. These data suggest that formation of early Wnt secretory vesicles is carefully regulated to ensure proper export of functional ligands.

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Homoharringtonine Induces Apoptosis in Human Colorectal Carcinoma HCT116 Cells Via Downregulation of Wnt/β‐Catenin Signaling Cascade

Park

Kwon

Kim

2019

Bulletin Korean Chem Soc

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Many tumors are relevant to the abnormal up-regulated transcriptional activity of β-catenin that interacts with T-cell factor (TCF) and lymphoid-enhancing factor (LEF) to induce the transcription of Wnt/β-catenin-response genes. [1][2][3] Since β-catenin is commonly dysregulated in colon cancer, targeting of β-catenin has been considered for therapeutic purposes to treat colon cancer. [4][5][6][7] In order to identify small molecules with anti-cancer action via inhibition of β-catenin activity, we screened 9939 compounds including 2320 FDA-approved drugs and the representative library (7619 compounds in Korea Chemical Bank; http://eng.chembank.org) and selected 416 compounds exhibiting β-catenin activity less than 80% of the control at 1 μM, and among them, 59 compounds exhibited the dose-dependent inhibitory activity in the concentration range from 0.01 to 1 μM. Then, through third and fourth screenings using human colon HCT116 cells, finally homoharringtonine (HHT; Figure 1(a)) was selected as a hit compound to strongly inhibit the β-catenin activity, the cell viability and the expression levels of LEF/TCF transcriptional target proteins (proto-oncogene c-Myc and cyclin D1) compared to others (Figure S1 in Supporting information).After approval by the US FDA in 2012, HHT has been used as a drug substance (omacetaxine mepesuccinate) for curing patients with chronic myeloid leukemia (CML). 8 Until now, a few studies have reported that HHT treatment and its combination with aclarubicin (anthracycline anticancer drug) resulted in the reduction and inhibition of β-catenin in multiple myeloma and acute myeloid leukemia, respectively. 9,10 Therefore, in this study, we investigated the hypothesis that apoptotic HHT in colon cancer could result from its inhibitory potential to Wnt/β-catenin signaling. 11 HCT116 cells have a heterozygous mutation of β-catenin, resulting in an increase in β-catenin-TCF4-mediated transcriptional activity among several types of colon cancer cells. 12,13 The potential of HHT to inhibit β-catenin activity in HCT116 cells was confirmed. In a dose-dependent manner, HHT significantly inhibited the β-catenin activity (Figure 1(b)) and the viability of HCT116 cells (Figure 1 (c)). The potent inhibitory action of HHT on the β-catenin activity was also revealed by evaluating the protein expression levels of c-Myc and cyclin D1 (Figure 1(d)). [14][15][16][17][18] How could HHT inhibit the β-catenin activity? To clarify this question, the protein levels of key factors in the Wnt/βcatenin signaling axis were investigated. Low-density lipoprotein receptor-related protein 6 (LRP6) involved in cytoskeleton dynamics has been shown to promote metastasis of colorectal cancer, 19 and its phosphorylation plays an important role to the activation of β-catenin. 20 After the activation of fizzled receptors, cytoplasmic phosphoprotein disheveled (Dvl) subsequently transmits the signal to the downstream factors in mammals. Over-expression of Dvl has been reported in several carcinomas, and the functional relevance...

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Discovery and Optimization of a Porcupine Inhibitor

Cited by 37 publications

References 22 publications

Exploration of the linkage elements of porcupine antagonists led to potent Wnt signaling pathway inhibitors

Exploration of the linkage elements of porcupine antagonists led to potent Wnt signaling pathway inhibitors

A Wntless–SEC12 complex on the ER membrane regulates early Wnt secretory vesicle assembly and mature ligand export

Homoharringtonine Induces Apoptosis in Human Colorectal Carcinoma HCT116 Cells Via Downregulation of Wnt/β‐Catenin Signaling Cascade

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