esther ong

National University of Singapore, Department of Biological Science, Post-Doc

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Papers by esther ong

Wnt addiction of genetically defined cancers reversed by PORCN inhibition

Oncogene, Aug 10, 2015

Enhanced sensitivity to Wnts is an emerging hallmark of a subset of cancers, defined in part by m... more Enhanced sensitivity to Wnts is an emerging hallmark of a subset of cancers, defined in part by mutations regulating the abundance of their receptors. Whether these mutations identify a clinical opportunity is an important question. Inhibition of Wnt secretion by blocking an essential post-translational modification, palmitoleation, provides a useful therapeutic intervention. We developed a novel potent, orally available PORCN inhibitor, ETC-1922159 (henceforth called ETC-159) that blocks the secretion and activity of all Wnts. ETC-159 is remarkably effective in treating RSPO-translocation bearing colorectal cancer (CRC) patient-derived xenografts. This is the first example of effective targeted therapy for this subset of CRC. Consistent with a central role of Wnt signaling in regulation of gene expression, inhibition of PORCN in RSPO3-translocated cancers causes a marked remodeling of the transcriptome, with loss of cell cycle, stem cell and proliferation genes, and an increase in differentiation markers. Inhibition of Wnt signaling by PORCN inhibition holds promise as differentiation therapy in genetically defined human cancers.

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Deep learning for de-convolution of Smad2 versus Smad3 binding sites

BMC Genomics

Background The transforming growth factor beta-1 (TGF β-1) cytokine exerts both pro-tumor and ant... more Background The transforming growth factor beta-1 (TGF β-1) cytokine exerts both pro-tumor and anti-tumor effects in carcinogenesis. An increasing body of literature suggests that TGF β-1 signaling outcome is partially dependent on the regulatory targets of downstream receptor-regulated Smad (R-Smad) proteins Smad2 and Smad3. However, the lack of Smad-specific antibodies for ChIP-seq hinders convenient identification of Smad-specific binding sites. Results In this study, we use localization and affinity purification (LAP) tags to identify Smad-specific binding sites in a cancer cell line. Using ChIP-seq data obtained from LAP-tagged Smad proteins, we develop a convolutional neural network with long-short term memory (CNN-LSTM) as a deep learning approach to classify a pool of Smad-bound sites as being Smad2- or Smad3-bound. Our data showed that this approach is able to accurately classify Smad2- versus Smad3-bound sites. We use our model to dissect the role of each R-Smad in the prog...

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Designing a leucine‐rich antibacterial nonapeptide with potent activity against mupirocin‐resistant MRSA via a structure–activity relationship study

Chemical Biology & Drug Design

Stepwise Evolution of Fragment Hits against MAPK Interacting Kinases 1 and 2

Journal of Medicinal Chemistry

Dual Specific Inhibitors Of The BCR-ABL and MNK Kinases As Potential Therapeutics For Blast Crisis Chronic Myeloid Leukemia

Blood

Pharmacologic inhibition of BCR-ABL by tyrosine kinase inhibitors (TKI) provides effective therap... more Pharmacologic inhibition of BCR-ABL by tyrosine kinase inhibitors (TKI) provides effective therapy for chronic phase but not blast crisis (BC) CML. The inability of TKIs to control BC CML is due to the reactivation of BCR-ABL through TKI resistance-conferring mutations, as well as the activation of alternative oncogenic pathways that mediate acquired leukemia stem cell (LSC) function and differentiation block in leukemic progenitors. Accordingly, the development of effective BC therapeutics will require reversing multiple contributors to the BC phenotype, and indicates that targeting BCR-ABL alone will not be sufficient to control BC CML. Indeed, despite the ability of third-generation TKIs to effectively inhibit the majority of clinically-relevant BCR-ABL kinase domain mutations, most patients with BC treated with these agents continue to relapse despite initial responses. Because our recent work has highlighted the importance of the MNK kinase-eIF4E axis in b-catenin-associated BC...

Correction to “Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3”

ACS Medicinal Chemistry Letters

The PDB ID given in the caption of Figure 3 is incorrect. The corrected caption can be seen below... more The PDB ID given in the caption of Figure 3 is incorrect. The corrected caption can be seen below: Figure 3. (A) Structure of compound 29 (orange) and SAM (pink) bound to SMYD3 (slate) (PDB ID: 6IJL). SMYD3 residues 3.5 Å away from 29 are shown in stick representation. (B) Overlay of structures of compounds 21 and 29 bound to SMYD3.

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Discovery of Irreversible Inhibitors Targeting Histone Methyl-transferase, SMYD3

ACS Medicinal Chemistry Letters

Fragment-based Discovery of a Small-molecule Protein Kinase C-iota Inhibitor Binding Post-kinase Domain Residues

ACS Medicinal Chemistry Letters

Designing an ultra-short antibacterial peptide with potent activity against Mupirocin-resistant MRSA

Chemical biology & drug design, Jan 13, 2018

Staphylococcus aureus is the pathogen responsible for the majority of human skin infections. In p... more Staphylococcus aureus is the pathogen responsible for the majority of human skin infections. In particular, the methicillin-resistant variety, MRSA, has become a global clinical concern. The extensive use of mupirocin, the first-line topical antibacterial drug of choice, has led to the emergence of mupirocin-resistant MRSA globally, resulting in the urgent need for a replacement. Antimicrobial peptides are deemed plausible candidates. Herein, we describe a structure-activity relationship approach in the design of an ultra-short peptide with potent anti-MRSA activity with a rapid, bactericidal mode of action. Coupled to a low cytotoxic activity, we believe our lead compound can be developed into a topical antibacterial agent to replace mupirocin as the first-line drug for treating MRSA skin infections.

Fragment-Based Drug Discovery of Potent Protein Kinase C Iota Inhibitors

Journal of medicinal chemistry, Jan 24, 2018

Protein kinase C iota (PKC-ι) is an atypical kinase implicated in the promotion of different canc... more Protein kinase C iota (PKC-ι) is an atypical kinase implicated in the promotion of different cancer types. A biochemical screen of a fragment library has identified several hits from which an azaindole-based scaffold was chosen for optimization. Driven by a structure-activity relationship and supported by molecular modeling, a weakly bound fragment was systematically grown into a potent and selective inhibitor against PKC-ι.

Structure-activity relationship studies of ultra-short peptides with potent activities against fluconazole-resistant Candida albicans

European journal of medicinal chemistry, Jan 25, 2018

Vulvovaginal candidiasis (VVC) is a genital fungal infection afflicting approximately 75% of wome... more Vulvovaginal candidiasis (VVC) is a genital fungal infection afflicting approximately 75% of women globally and is primarily caused by the yeast Candida albicans. The extensive use of fluconazole, the first-line antifungal drug of choice, has led to the emergence of fluconazole-resistant C. albicans, creating a global clinical concern. This, coupled to the lack of new antifungal drugs entering the market over the past decade, has made it imperative for the introduction of new antifungal drug classes. Peptides with antifungal properties are deemed potential drug candidates due to their rapid membrane-disrupting mechanism of action. By specifically targeting and rapidly disrupting fungal membranes, they reduce the chances of resistance development and treatment duration. In a previous screening campaign involving an antimicrobial peptide library, we identified an octapeptide (IKIKIKIK-NH) with potent activity against C. albicans. Herein, we report a structure-activity relationship stu...

Optimization of Selective Mitogen-activated Protein Kinase Interacting Kinases 1 and 2 (MNK1/2) Inhibitors for the treatment of Blast Crisis Leukemia

Journal of medicinal chemistry, Jan 23, 2018

Chronic Myeloid Leukemia (CML) is a myeloproliferative disease caused by bcr-abl1, a constitutive... more Chronic Myeloid Leukemia (CML) is a myeloproliferative disease caused by bcr-abl1, a constitutively active tyrosine kinase fusion gene responsible for an abnormal proliferation of leukemic stem cells (LSCs). Inhibition of BCR-ABL1 kinase activity offers long term relief to CML patients. However, for a proportion of them, BCR-ABL1 inhibition will become ineffective at treating the disease and CML will progress to blast crisis (BC) CML with poor prognosis. BC-CML is often associated with excessive phosphorylated eukaryotic translation initiation factor 4E (eIF4E) which renders LSCs capable of proliferating via self-renewal, oblivious to BCR-ABL1 inhibition. In vivo, eIF4E is exclusively phosphorylated on Ser209 by MNK1/2. Consequently, a selective inhibitor of MNK1/2 should reduce the level of phosphorylated eIF4E and re-sensitize LSCs to BCR-ABL1 inhibition, thus hindering the proliferation of BC LSCs. We report herein the structure activity relationships and pharmacokinetic properti...

Abstract 3819: Identification and quantification of isoforms of eukaryotic initiation factor 4E as biomarker in Mnk inhibitor-treated mouse model by capillary-based immunoassay platform

Cancer Research

Abstract 1172:In vivopharmacokinetic properties and antitumor efficacy of porcupine lead inhibitors in the orthotopic murine MMTV-Wnt1 breast tumor model and the human HPAF-II pancreatic xenograft mouse model

Cancer Research

Screening for a Potent Antibacterial Peptide to Treat Mupirocin-Resistant MRSA Skin Infections

International Journal of Peptide Research and Therapeutics, 2017

Abstract 2137: Discovery of dual MNK 1 and 2 and BCR-ABL kinase inhibitors for the treatment of blast crisis chronic myeloid leukemia

Cancer Research, 2016

Abstract 2134: Rational design of selective MNK 1 and 2 kinase inhibitors for the treatment of blast crisis chronic myeloid leukemia patients

Cancer Research, 2016

An FDA-Drug Library Screen for Compounds with Bioactivities against Meticillin-Resistant Staphylococcus aureus (MRSA)

Antibiotics, 2015

The lack of new antibacterial drugs entering the market and their misuse have resulted in the eme... more The lack of new antibacterial drugs entering the market and their misuse have resulted in the emergence of drug-resistant bacteria, posing a major health crisis worldwide. In particular, meticillin-resistant Staphylococcus aureus (MRSA), a pathogen responsible for numerous human infections, has become endemic in hospitals worldwide. Drug repurposing, the finding of new therapeutic indications for approved drugs, is deemed a plausible solution to accelerate drug discovery and development in this area. Towards this end, we screened 1163 drugs approved by the Food and Drug Administration (FDA) for bioactivities against MRSA in a 10 μM single-point assay. After excluding known antibiotics and antiseptics, six compounds were identified and their MICs were determined against a panel of clinical MRSA strains. A toxicity assay using human keratinocytes was also conducted to gauge their potential for repurposing as topical agents for treating MRSA skin infections.

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Abstract 4449: A novel Porcupine inhibitor is effective in the treatment of cancers with RNF43 mutations

Cancer Research, 2015

Feedback regulation on PTEN/AKT pathway by the ER stress kinase PERK mediated by interaction with the Vault complex

Cellular Signalling, 2015

The high proliferation rate of cancer cells, together with environmental factors such as hypoxia ... more The high proliferation rate of cancer cells, together with environmental factors such as hypoxia and nutrient deprivation can cause Endoplasmic Reticulum (ER) stress. The protein kinase PERK is an essential mediator in one of the three ER stress response pathways. Genetic and pharmacological inhibition of PERK has been reported to limit tumor growth in xenograft models. Here we provide evidence that inactive PERK interacts with the nuclear pore-associated Vault complex protein and that this compromises Vault-mediated nuclear transport of PTEN. Pharmacological inhibition of PERK under ER stress results is abnormal sequestration of the Vault complex, leading to increased cytoplasmic PTEN activity and lower AKT activation. As the PI3K/PTEN/AKT pathway is crucial for many aspects of cell growth and survival, this unexpected effect of PERK inhibitors on AKT activity may have implications for their potential use as therapeutic agents.

Wnt addiction of genetically defined cancers reversed by PORCN inhibition

Oncogene, Aug 10, 2015

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Deep learning for de-convolution of Smad2 versus Smad3 binding sites

BMC Genomics

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Designing a leucine‐rich antibacterial nonapeptide with potent activity against mupirocin‐resistant MRSA via a structure–activity relationship study

Chemical Biology & Drug Design

Stepwise Evolution of Fragment Hits against MAPK Interacting Kinases 1 and 2

Journal of Medicinal Chemistry

Dual Specific Inhibitors Of The BCR-ABL and MNK Kinases As Potential Therapeutics For Blast Crisis Chronic Myeloid Leukemia

Blood

Correction to “Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3”

ACS Medicinal Chemistry Letters

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Discovery of Irreversible Inhibitors Targeting Histone Methyl-transferase, SMYD3

ACS Medicinal Chemistry Letters

Fragment-based Discovery of a Small-molecule Protein Kinase C-iota Inhibitor Binding Post-kinase Domain Residues

ACS Medicinal Chemistry Letters

Designing an ultra-short antibacterial peptide with potent activity against Mupirocin-resistant MRSA

Chemical biology & drug design, Jan 13, 2018

Fragment-Based Drug Discovery of Potent Protein Kinase C Iota Inhibitors

Journal of medicinal chemistry, Jan 24, 2018

Structure-activity relationship studies of ultra-short peptides with potent activities against fluconazole-resistant Candida albicans

European journal of medicinal chemistry, Jan 25, 2018

Optimization of Selective Mitogen-activated Protein Kinase Interacting Kinases 1 and 2 (MNK1/2) Inhibitors for the treatment of Blast Crisis Leukemia

Journal of medicinal chemistry, Jan 23, 2018

Abstract 3819: Identification and quantification of isoforms of eukaryotic initiation factor 4E as biomarker in Mnk inhibitor-treated mouse model by capillary-based immunoassay platform

Cancer Research

Screening for a Potent Antibacterial Peptide to Treat Mupirocin-Resistant MRSA Skin Infections

International Journal of Peptide Research and Therapeutics, 2017

Abstract 2137: Discovery of dual MNK 1 and 2 and BCR-ABL kinase inhibitors for the treatment of blast crisis chronic myeloid leukemia

Cancer Research, 2016

Abstract 2134: Rational design of selective MNK 1 and 2 kinase inhibitors for the treatment of blast crisis chronic myeloid leukemia patients

Cancer Research, 2016

An FDA-Drug Library Screen for Compounds with Bioactivities against Meticillin-Resistant Staphylococcus aureus (MRSA)

Antibiotics, 2015

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Abstract 4449: A novel Porcupine inhibitor is effective in the treatment of cancers with RNF43 mutations

Cancer Research, 2015

Feedback regulation on PTEN/AKT pathway by the ER stress kinase PERK mediated by interaction with the Vault complex

Cellular Signalling, 2015

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