Displaying publications 1 - 20 of 32 in total

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  1. Metallointercalator [Ru(dppz)2(PIP)]2+ Renders BRCA Wild-Type Triple-Negative Breast Cancer Cells Hypersensitive to PARP Inhibition
    Yusoh NA, Leong SW, Chia SL, Harun SN, Rahman MBA, Vallis KA, et al.
    ACS Chem. Biol., 2020 02 21;15(2):378-387.
    PMID: 31898884 DOI: 10.1021/acschembio.9b00843
    There is a need to improve and extend the use of clinically approved poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi), including for BRCA wild-type triple-negative breast cancer (TNBC). The demonstration that ruthenium(II) polypyridyl complex (RPC) metallointercalators can rapidly stall DNA replication fork progression provides the rationale for their combination alongside DNA damage response (DDR) inhibitors to achieve synergism in cancer cells. The aim of the present study was to evaluate use of the multi-intercalator [Ru(dppz)2(PIP)]2+ (dppz = dipyrido[3,2-a:2',3'-c]phenazine, PIP = (2-(phenyl)imidazo[4,5-f][1,10]phenanthroline, Ru-PIP) alongside the PARPi olaparib and NU1025. Cell proliferation and clonogenic survival assays indicated a synergistic relationship between Ru-PIP and olaparib in MDA-MB-231 TNBC and MCF7 human breast cancer cells. Strikingly, low dose Ru-PIP renders both cell lines hypersensitive to olaparib, with a >300-fold increase in olaparib potency in TNBC, the largest nongenetic PARPi enhancement effect described to date. A negligible impact on the viability of normal human fibroblasts was observed for any combination tested. Increased levels of DNA double-strand break (DSB) damage and olaparib abrogation of Ru-PIP-activated pChk1 signaling are consistent with PARPi-facilitated collapse of Ru-PIP-associated stalled replication forks. This results in enhanced G2/M cell-cycle arrest, apoptosis, and decreased cell motility for the combination treatment compared to single-agent conditions. This work establishes that an RPC metallointercalator can be combined with PARPi for potent synergy in BRCA-proficient breast cancer cells, including TNBC.
  2. Fulltext Persistent Newcastle disease virus infection in bladder cancer cells is associated with putative pro-survival and anti-viral transcriptomic changes
    Chan LC, Kalyanasundram J, Leong SW, Masarudin MJ, Veerakumarasivam A, Yusoff K, et al.
    BMC Cancer, 2021 May 27;21(1):625.
    PMID: 34044804 DOI: 10.1186/s12885-021-08345-y
    BACKGROUND: Newcastle disease virus (NDV) is an oncolytic virus with excellent selectivity against cancer cells, both in vitro and in vivo. Unfortunately, prolonged in vitro NDV infection results in the development of persistent infection in the cancer cells which are then able to resist NDV-mediated oncolysis. However, the mechanism of persistency of infection remains poorly understood.

    METHODS: In this study, we established persistently NDV-infected EJ28 bladder cancer cells, designated as EJ28P. Global transcriptomic analysis was subsequently carried out by microarray analysis. Differentially expressed genes (DEGs) between EJ28 and EJ28P cells identified by the edgeR program were further analysed by Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) analyses. In addition, the microarray data were validated by RT-qPCR.

    RESULTS: Persistently NDV-infected EJ28 bladder cancer cells were successfully established and confirmed by flow cytometry. Microarray analysis identified a total of 368 genes as differentially expressed in EJ28P cells when compared to the non-infected EJ28 cells. GSEA revealed that the Wnt/β-catenin and KRAS signalling pathways were upregulated while the TGF-β signalling pathway was downregulated. Findings from this study suggest that the upregulation of genes that are associated with cell growth, pro-survival, and anti-apoptosis may explain the survivability of EJ28P cells and the development of persistent infection of NDV.

    CONCLUSIONS: This study provides insights into the transcriptomic changes that occur and the specific signalling pathways that are potentially involved in the development and maintenance of NDV persistency of infection in bladder cancer cells. These findings warrant further investigation and is crucial towards the development of effective NDV oncolytic therapy against cancer.

  3. Fulltext Assembly and stability of Salmonella enterica ser. Typhi TolC protein in POPE and DMPE
    Leong SW, Lim TS, Tye GJ, Ismail A, Aziah I, Choong YS
    J Biol Phys, 2014 Sep;40(4):387-400.
    PMID: 25011632 DOI: 10.1007/s10867-014-9357-9
    In this work we assessed the suitability of two different lipid membranes for the simulation of a TolC protein from Salmonella enterica serovar Typhi. The TolC protein family is found in many pathogenic Gram-negative bacteria including Vibrio cholera and Pseudomonas aeruginosa and acts as an outer membrane channel for expulsion of drug and toxin from the cell. In S. typhi, the causative agent for typhoid fever, the TolC outer membrane protein is an antigen for the pathogen. The lipid environment is an important modulator of membrane protein structure and function. We evaluated the conformation of the TolC protein in the presence of DMPE and POPE bilayers using molecular dynamics simulation. The S. typhi TolC protein exhibited similar conformational dynamics to TolC and its homologues. Conformational flexibility of the protein is seen in the C-terminal, extracellular loops, and α-helical region. Despite differences in the two lipids, significant similarities in the motion of the protein in POPE and DMPE were observed, including the rotational motion of the C-terminal residues and the partially open extracellular loops. However, analysis of the trajectories demonstrated effects of hydrophobic matching of the TolC protein in the membrane, particularly in the lengthening of the lipids and subtle movements of the protein's β-barrel towards the lower leaflet in DMPE. The study exhibited the use of molecular dynamics simulation in revealing the differential effect of membrane proteins and lipids on each other. In this study, POPE is potentially a more suitable model for future simulation of the S. typhi TolC protein.
  4. Integration of molecular dynamics simulation and hotspot residues grafting for de novo scFv design against Salmonella Typhi TolC protein
    Leong SW, Lim TS, Ismail A, Choong YS
    J. Mol. Recognit., 2018 05;31(5):e2695.
    PMID: 29230887 DOI: 10.1002/jmr.2695
    With the development of de novo binders for protein targets from non-related scaffolds, many possibilities for therapeutics and diagnostics have been created. In this study, we described the use of de novo design approach to create single-chain fragment variable (scFv) for Salmonella enterica subspecies enterica serovar Typhi TolC protein. Typhoid fever is a global health concern in developing and underdeveloped countries. Rapid typhoid diagnostics will improve disease management and therapy. In this work, molecular dynamics simulation was first performed on a homology model of TolC protein in POPE membrane bilayer to obtain the central structure that was subsequently used as the target for scFv design. Potential hotspot residues capable of anchoring the binders to the target were identified by docking "disembodied" amino acid residues against TolC surface. Next, scFv scaffolds were selected from Protein Data Bank to harbor the computed hotspot residues. The hotspot residues were then incorporated into the scFv scaffold complementarity determining regions. The designs recapitulated binding energy, shape complementarity, and interface surface area of natural protein-antibody interfaces. This approach has yielded 5 designs with high binding affinity against TolC that may be beneficial for the future development of antigen-based detection agents for typhoid diagnostics.
  5. Learning to travel: reducing the health risks of study abroad opportunities
    Flaherty GT, Leong SW, Geoghegan R
    J Travel Med, 2018 01 01;25(1).
    PMID: 30239844 DOI: 10.1093/jtm/tay085
  6. Development of diarylpentadienone analogues as alpha-glucosidase inhibitor: Synthesis, in vitro biological and in vivo toxicity evaluations, and molecular docking analysis
    Abdullah MA, Lee YR, Mastuki SN, Leong SW, Wan Ibrahim WN, Mohammad Latif MA, et al.
    Bioorg Chem, 2020 11;104:104277.
    PMID: 32971414 DOI: 10.1016/j.bioorg.2020.104277
    A series of aminated- (1-9) and sulfonamide-containing diarylpentadienones (10-18) were synthesized, structurally characterized, and evaluated for their in vitro anti-diabetic potential on α-glucosidase and DPP-4 enzymes. It was found that all the new molecules were non-associated PAINS compounds. The sulfonamide-containing series (compounds 10-18) selectively inhibited α-glucosidase over DPP-4, in which compound 18 demonstrated the highest activity with an IC50 value of 5.69 ± 0.5 µM through a competitive inhibition mechanism. Structure-activity relationship (SAR) studies concluded that the introduction of the trifluoromethylbenzene sulfonamide moiety was essential for the suppression of α-glucosidase. The most active compound 18, was then further tested for in vivo toxicities using the zebrafish animal model, with no toxic effects detected in the normal embryonic development, blood vessel formation, and apoptosis of zebrafish. Docking simulation studies were also carried out to better understand the binding interactions of compound 18 towards the homology modeled α -glucosidase and the human lysosomal α -glucosidase enzymes. The overall results suggest that the new sulfonamide-containing diarylpentadienones, compound 18, could be a promising candidate in the search for a new α-glucosidase inhibitor, and can serve as a basis for further studies involving hit-to-lead optimization, in vivo efficacy and safety assessment in an animal model and mechanism of action for the treatment of T2DM patients.
  7. Fulltext Preliminary insight on diarylpentanoids as potential antimalarials: In silico, in vitro pLDH and in vivo zebrafish toxicity assessment
    Ramli AH, Swain P, Mohd Fahmi MSA, Abas F, Leong SW, Tejo BA, et al.
    Heliyon, 2024 Mar 15;10(5):e27462.
    PMID: 38495201 DOI: 10.1016/j.heliyon.2024.e27462
    Malaria remains a major public health problem worldwide, including in Southeast Asia. Chemotherapeutic agents such as chloroquine (CQ) are effective, but problems with drug resistance and toxicity have necessitated a continuous search for new effective antimalarial agents. Here we report on a virtual screening of ∼300 diarylpentanoids and derivatives, in search of potential Plasmodium falciparum lactate dehydrogenase (PfLDH) inhibitors with acceptable drug-like properties. Several molecules with binding affinities comparable to CQ were chosen for in vitro validation of antimalarial efficacy. Among them, MS33A, MS33C and MS34C are the most promising against CQ-sensitive (3D7) with EC50 values of 1.6, 2.5 and 3.1 μM, respectively. Meanwhile, MS87 (EC50 of 1.85 μM) shown the most active against the CQ-resistant Gombak A strain, and MS33A and MS33C the most effective P. knowlesi inhibitors (EC50 of 3.6 and 5.1 μM, respectively). The in vitro cytotoxicity of selected diarylpentanoids (MS33A, MS33C, MS34C and MS87) was tested on Vero mammalian cells to evaluate parasite selectivity (SI), showing moderate to low cytotoxicity (CC50 > 82 μM). In addition, MS87 exhibited a high SI and the lowest resistance index (RI), suggesting that MS87 may exert effective parasite inhibition with low resistance potential in the CQ-resistant P. falciparum strain. Furthermore, the in vivo toxicity of the molecules on early embryonic development, the cardiovascular system, heart rate, motor activity and apoptosis were assessed in a zebrafish animal model. The overall results indicate the preliminary potential of diarylpentanoids, which need further investigation for their development as new antimalarial agents.
  8. Fulltext Synthesis and sar study of diarylpentanoid analogues as new anti-inflammatory agents
    Leong SW, Faudzi SM, Abas F, Aluwi MF, Rullah K, Wai LK, et al.
    Molecules, 2014 Oct 09;19(10):16058-81.
    PMID: 25302700 DOI: 10.3390/molecules191016058
    A series of ninety-seven diarylpentanoid derivatives were synthesized and evaluated for their anti-inflammatory activity through NO suppression assay using interferone gamma (IFN-γ)/lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Twelve compounds (9, 25, 28, 43, 63, 64, 81, 83, 84, 86, 88 and 97) exhibited greater or similar NO inhibitory activity in comparison with curcumin (14.7 ± 0.2 µM), notably compounds 88 and 97, which demonstrated the most significant NO suppression activity with IC50 values of 4.9 ± 0.3 µM and 9.6 ± 0.5 µM, respectively. A structure-activity relationship (SAR) study revealed that the presence of a hydroxyl group in both aromatic rings is critical for bioactivity of these molecules. With the exception of the polyphenolic derivatives, low electron density in ring-A and high electron density in ring-B are important for enhancing NO inhibition. Meanwhile, pharmacophore mapping showed that hydroxyl substituents at both meta- and para-positions of ring-B could be the marker for highly active diarylpentanoid derivatives.
  9. 2-Benzoyl-6-benzylidenecyclohexanone analogs as potent dual inhibitors of acetylcholinesterase and butyrylcholinesterase
    Leong SW, Abas F, Lam KW, Shaari K, Lajis NH
    Bioorg Med Chem, 2016 08 15;24(16):3742-51.
    PMID: 27328658 DOI: 10.1016/j.bmc.2016.06.016
    In the present study, a series of 2-benzoyl-6-benzylidenecyclohexanone analogs have been synthesized and evaluated for their anti-cholinesterase activity. Among the forty-one analogs, four compounds (38, 39, 40 and 41) have been identified as lead compounds due to their highest inhibition on both AChE and BChE activities. Compounds 39 and 40 in particular exhibited highest inhibition on both AChE and BChE with IC50 values of 1.6μM and 0.6μM, respectively. Further structure-activity relationship study suggested that presence of a long-chain heterocyclic in one of the rings played a critical role in the dual enzymes' inhibition. The Lineweaver-Burk plots and docking results suggest that both compounds could simultaneously bind to the PAS and CAS regions of the enzyme. ADMET analysis further confirmed the therapeutic potential of both compounds based upon their high BBB-penetrating. Thus, 2-benzoyl-6-benzylidenecyclohexanone containing long-chain heterocyclic amine analogs represent a new class of cholinesterase inhibitor, which deserve further investigation for their development into therapeutic agents for cognitive diseases such as Alzheimer.
  10. Nitric oxide inhibitory activity and antioxidant evaluations of 2-benzoyl-6-benzylidenecyclohexanone analogs, a novel series of curcuminoid and diarylpentanoid derivatives
    Leong SW, Mohd Faudzi SM, Abas F, Mohd Aluwi MF, Rullah K, Lam KW, et al.
    Bioorg Med Chem Lett, 2015 Aug 15;25(16):3330-7.
    PMID: 26071636 DOI: 10.1016/j.bmcl.2015.05.056
    A series of twenty-four 2-benzoyl-6-benzylidenecyclohexanone analogs were synthesized and evaluated for their nitric oxide inhibition and antioxidant activity. Six compounds (3, 8, 10, 17, 18 and 19) were found to exhibit significant NO inhibitory activity in LPS/IFN-induced RAW 264.7 macrophages, of which compound 10 demonstrated the highest activity with the IC50 value of 4.2 ± 0.2 μM. Furthermore, two compounds (10 and 17) displayed antioxidant activity upon both the DPPH scavenging and FRAP analyses. However, none of the 2-benzoyl-6-benzylidenecyclohexanone analogs significantly scavenged NO radical. Structure-activity comparison suggested that 3,4-dihydroxylphenyl ring is crucial for bioactivities of the 2-benzoyl-6-benzylidenecyclohexanone analogs. The results from this study and the reports from previous studies indicated that compound 10 could be a candidate for further investigation on its potential as a new anti-inflammatory agent.
  11. Synthesis of unsymmetrical monocarbonyl curcumin analogues with potent inhibition on prostaglandin E2 production in LPS-induced murine and human macrophages cell lines
    Mohd Aluwi MF, Rullah K, Yamin BM, Leong SW, Abdul Bahari MN, Lim SJ, et al.
    Bioorg Med Chem Lett, 2016 05 15;26(10):2531-8.
    PMID: 27040659 DOI: 10.1016/j.bmcl.2016.03.092
    The syntheses and bioactivities of symmetrical curcumin and its analogues have been the subject of interest by many medicinal chemists and pharmacologists over the years. To improve our understanding, we have synthesized a series of unsymmetrical monocarbonyl curcumin analogues and evaluated their effects on prostaglandin E2 production in lipopolysaccharide-induced RAW264.7 and U937 cells. Initially, compounds 8b and 8c exhibited strong inhibition on the production of PGE2 in both LPS-stimulated RAW264.7 (8b, IC50=12.01μM and 8c, IC50=4.86μM) and U937 (8b, IC50=3.44μM and 8c, IC50=1.65μM) cells. Placing vanillin at position Ar2 further improved the potency when both compounds 15a and 15b significantly lowered the PGE2 secretion level (RAW264.7: 15a, IC50=0.78μM and 15b, IC50=1.9μM while U937: 15a, IC50=0.95μM and 15b, IC50=0.92μM). Further experiment showed that compounds 8b, 8c, 15a and 15b did not target the activity of downstream inflammatory COX-2 mediator. Finally, docking simulation on protein targets COX-2, IKK-β, ERK, JNK2, p38α and p38β were performed using the conformation of 15a determined by single-crystal XRD.
  12. Flavonoid diversity and roles in the lipopolysaccharide-mediated inflammatory response of monocytes and macrophages
    Rullah K, Shamsudin NF, Koeberle A, Tham CL, Fasihi Mohd Aluwi MF, Leong SW, et al.
    Future Med Chem, 2024 Jan;16(1):75-99.
    PMID: 38205612 DOI: 10.4155/fmc-2023-0174
    Targeting lipopolysaccharide (LPS)/toll-like receptor 4 signaling in mononuclear phagocytes has been explored for the treatment of inflammation and inflammation-related disorders. However, only a few key targets have been translated into clinical applications. Flavonoids, a class of ubiquitous plant secondary metabolites, possess a privileged scaffold which serves as a valuable template for designing pharmacologically active compounds directed against diseases with inflammatory components. This perspective provides a general overview of the diversity of flavonoids and their multifaceted mechanisms that interfere with LPS-induced signaling in monocytes and macrophages. Focus is placed on flavonoids targeting MD-2, IκB kinases, c-Jun N-terminal kinases, extracellular signal-regulated kinase, p38 MAPK and PI3K/Akt or modulating LPS-related gene expression.
  13. Fulltext Evaluation of nutritional status among a group of young Chinese adults in Kuala Lumpur, Malaysia
    Karim N, Leong SW
    Asia Pac J Clin Nutr, 2000 Jun;9(2):82-6.
    PMID: 24394392
    A nutritional status study was carried out among a group of young Chinese adults, aged between 19 and 25, in Kuala Lumpur, Malaysia. Subjects comprised 108 young adults (55 women, 53 men) who were students at two institutes of higher learning. Physical characteristics were evaluated by anthropometric measurements while food intake was determined with a 3-day food record. Blood cholesterol and triglyceride were assessed using the Reflotron analyser. Birthweight was obtained from birth certificates or by proxy. The results showed that the mean body mass index (BMI) for men and women was 21.4 ± 3.3 and 20.0 ± 2.0, respectively, indicating normal weight. Further analysis of BMI classification demonstrated that 28% of men and 39% of women were underweight, 11% of men and 2% of women were overweight while 2% of men were obese. Mean waist-to-hip ratio showed that the subjects had a low risk of developing cardiovascular disease (0.72 ± 0.03 women; 0.81 ± 0.05 men). Mean energy intake was 8841 ± 1756 kJ per day for men and 6426 ± 1567 kJ per day for women. Closer analysis of energy intake of the subjects showed that 86% of men and 91% of women were consuming below the Malaysian recommendation for energy. Nutrients found to be deficient in at least one third of women were calcium, vitamin A, niacin and iron. Mean cholesterol intake in the diet was 278.7 ± 108.7 mg in men and 207.0 ± 82.5 mg in women and there was a significant difference between genders. Blood cholesterol and triglyceride levels were 3.88 ± 0.76 mmol/L and 1.08 ± 0.33 mmol/L, respectively in men, while these levels were lower in women, 3.87 ± 0.80 mmol/L for cholesterol and 0.99 ± 0.29 mmol/L for triglyceride. A general trend of higher mean blood cholesterol and triglyceride levels was shown in adults who were born with lower birthweights.
  14. Improved Fab presentation on phage surface with the use of molecular chaperone coplasmid system
    Loh Q, Leong SW, Tye GJ, Choong YS, Lim TS
    Anal Biochem, 2015 May 15;477:56-61.
    PMID: 25769419 DOI: 10.1016/j.ab.2015.02.026
    The low presentation efficiency of Fab (fragment antigen binding) fragments during phage display is largely due to the complexity of disulphide bond formation. This can result in the presentation of Fab fragments devoid of a light chain during phage display. Here we propose the use of a coplasmid system encoding several molecular chaperones (DsbA, DsbC, FkpA, and SurA) to improve Fab packaging. A comparison was done using the Fab fragment from IgG and IgD. We found that the use of the coplasmid during phage packaging was able to improve the presentation efficiency of the Fab fragment on phage surfaces. A modified version of panning using the coplasmid system was evaluated and was successful at enriching Fab binders. Therefore, the coplasmid system would be an attractive alternative for improved Fab presentation for phage display.
  15. Fulltext Management of asthma in adults in primary care
    Ban A, Omar A, Chong LY, Lockman H, Ida Zaliza ZA, Ali I, et al.
    Malays Fam Physician, 2018;13(3):20-26.
    PMID: 30800229 MyJurnal
    Asthma is a chronic inflammatory disease of the airway which is often misdiagnosed and undertreated. Early diagnosis and vigilant asthma control are crucial to preventing permanent airway damage, improving quality of life and reducing healthcare burdens. The key approaches to asthma management should include patient empowerment through health education and self-management and, an effective patient-healthcare provider partnership.
  16. Fulltext Lung transplantation for interstitial lung disease: evolution over three decades
    Leong SW, Bos S, Lordan JL, Nair A, Fisher AJ, Meachery G
    BMJ Open Respir Res, 2023 Feb;10(1).
    PMID: 36854571 DOI: 10.1136/bmjresp-2022-001387
    BACKGROUND: Interstitial lung disease (ILD) has emerged as the most common indication for lung transplantation globally. However, post-transplant survival varies depending on the underlying disease phenotype and comorbidities. This study aimed to describe the demographics, disease classification, outcomes and factors associated with post-transplant survival in a large single-centre cohort.

    METHODS: Data were retrospectively assessed for 284 recipients who underwent lung transplantation for ILD in our centre between 1987 and 2020. Patient characteristics and outcomes were stratified by three eras: 1987-2000, 2001-2010 and 2011-2020.

    RESULTS: Median patients' age at time of transplantation was significantly higher in the most recent decade (56 (51-61) years, p<0.0001). Recipients aged over 50 years had worse overall survival compared with younger patients (adjusted HR, aHR 2.36, 95% CI 1.55 to 3.72, p=0.0001). Better survival was seen with bilateral versus single lung transplantation in patients younger than 50 years (log-rank p=0.0195). However, this survival benefit was no longer present in patients aged over 50 years. Reduced survival was observed in fibrotic non-specific interstitial pneumonia compared with idiopathic pulmonary fibrosis, which remained the most common indication throughout (aHR 2.61, 95% CI 1.40 to 4.60, p=0.0015).

    CONCLUSION: In patients transplanted for end-stage ILD, older age and fibrotic non-specific interstitial pneumonia were associated with poorer post-transplant survival. The benefit of bilateral over single lung transplantation diminished with increasing age, suggesting that single lung transplantation might still be a feasible option in older candidates.

  17. Travellers with type 1 diabetes: questionnaire development and descriptive analysis of knowledge and practices
    Flaherty GT, Leong SW, Finn Y, Sulaiman LH, Noone C
    J Travel Med, 2020 Sep 26;27(6).
    PMID: 32634210 DOI: 10.1093/jtm/taaa110
    BACKGROUND: Little is known about the awareness of travellers with diabetes about the health effects of international travel. This study aimed to design and validate a questionnaire to examine the travel health knowledge, attitudes and practices of people living with type 1 diabetes.

    METHODS: A set of 74 items based on a conceptual framework analysis underwent revision and its content validity was established. Items were grouped into three domains. A development study was conducted to establish evidence regarding their factorial structure. A construct validation study was then conducted in which the retained items were tested in an independent sample using confirmatory factor analysis (CFA).

    RESULTS: Four factors emerged from our development study and were labelled as pre-travel preparation-insect bites, pre-travel preparation-consultation, insulin and glycaemic control and travel risk behaviour. A CFA confirmed the factorial structure identified in the development study in an independent sample. Each factor loading had a significant (P 

  18. Erratum to: Zebrafish phenotypic screen identifies novel Notch antagonists
    Velaithan V, Okuda KS, Ng MF, Samat N, Leong SW, Faudzi SM, et al.
    Invest New Drugs, 2017 04;35(2):250.
    PMID: 28185040 DOI: 10.1007/s10637-017-0437-0
  19. Zebrafish phenotypic screen identifies novel Notch antagonists
    Velaithan V, Okuda KS, Ng MF, Samat N, Leong SW, Faudzi SM, et al.
    Invest New Drugs, 2017 04;35(2):166-179.
    PMID: 28058624 DOI: 10.1007/s10637-016-0423-y
    Zebrafish represents a powerful in vivo model for phenotype-based drug discovery to identify clinically relevant small molecules. By utilizing this model, we evaluated natural product derived compounds that could potentially modulate Notch signaling that is important in both zebrafish embryogenesis and pathogenic in human cancers. A total of 234 compounds were screened using zebrafish embryos and 3 were identified to be conferring phenotypic alterations similar to embryos treated with known Notch inhibitors. Subsequent secondary screens using HEK293T cells overexpressing truncated Notch1 (HEK293TΔE) identified 2 compounds, EDD3 and 3H4MB, to be potential Notch antagonists. Both compounds reduced protein expression of NOTCH1, Notch intracellular domain (NICD) and hairy and enhancer of split-1 (HES1) in HEK293TΔE and downregulated Notch target genes. Importantly, EDD3 treatment of human oral cancer cell lines demonstrated reduction of Notch target proteins and genes. EDD3 also inhibited proliferation and induced G0/G1 cell cycle arrest of ORL-150 cells through inducing p27KIP1. Our data demonstrates the utility of the zebrafish phenotypic screen and identifying EDD3 as a promising Notch antagonist for further development as a novel therapeutic agent.
  20. Novel 2-Benzoyl-6-(2,3-Dimethoxybenzylidene)-Cyclohexenol Confers Selectivity toward Human MLH1 Defective Cancer Cells through Synthetic Lethality
    Song DSS, Leong SW, Ng KW, Abas F, Shaari K, Leong CO, et al.
    SLAS Discov, 2019 06;24(5):548-562.
    PMID: 30897027 DOI: 10.1177/2472555219831405
    DNA mismatch repair (MMR) deficiency has been associated with a higher risk of developing colorectal, endometrial, and ovarian cancer, and confers resistance in conventional chemotherapy. In addition to the lack of treatment options that work efficaciously on these MMR-deficient cancer patients, there is a great need to discover new drug leads for this purpose. In this study, we screened through a library of commercial and semisynthetic natural compounds to identify potential synthetic lethal drugs that may selectively target MLH1 mutants using MLH1 isogenic colorectal cancer cell lines and various cancer cell lines with known MLH1 status. We identified a novel diarylpentanoid analogue, 2-benzoyl-6-(2,3-dimethoxybenzylidene)-cyclohexenol, coded as AS13, that demonstrated selective toxicity toward MLH1-deficient cancer cells. Subsequent analysis suggested AS13 induced elevated levels of oxidative stress, resulting in DNA damage where only the proficient MLH1 cells were able to be repaired and hence escaping cellular death. While AS13 is modest in potency and selectivity, this discovery has the potential to lead to further drug development that may offer better treatment options for cancer patients with MLH1 deficiency.
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