Hui-Yi Shiao
National Health Research Institutes
Network
Latest external collaboration on country level. Dive into details by clicking on the dots.
Publication
Featured researches published by Hui-Yi Shiao.
Journal of Medicinal Chemistry | 2010
Jiann-Yih Yeh; Mohane Selvaraj Coumar; Jim-Tong Horng; Hui-Yi Shiao; Fu-Ming Kuo; Hui-Ling Lee; In-Chun Chen; Chun-Wei Chang; Wen-Fang Tang; Sung-Nain Tseng; Chi-Jene Chen; Shin-Ru Shih; John T.-A. Hsu; Chun-Chen Liao; Yu-Sheng Chao; Hsing-Pang Hsieh
By using a cell-based high throughput screening campaign, a novel angelicin derivative 6a was identified to inhibit influenza A (H1N1) virus induced cytopathic effect in Madin-Darby canine kidney cell culture in low micromolar range. Detailed structure-activity relationship studies of 6a revealed that the angelicin scaffold is essential for activity in pharmacophore B, while meta-substituted phenyl/2-thiophene rings are optimal in pharmacophore A and C. The optimized lead 4-methyl-9-phenyl-8-(thiophene-2-carbonyl)-furo[2,3-h]chromen-2-one (8g, IC(50) = 70 nM) showed 64-fold enhanced activity compared to the high throughput screening (HTS) hit 6a. Also, 8g was found effective in case of influenza A (H3N2) and influenza B virus strains similar to approved anti-influenza drug zanamivir (4). Preliminary mechanistic studies suggest that these compounds act as anti-influenza agents by inhibiting ribonucleoprotein (RNP) complex associated activity and have the potential to be developed further, which could form the basis for developing additional defense against influenza pandemics.
Expert Opinion on Investigational Drugs | 2014
Chieh‐Chien Lee; Hui-Yi Shiao; Wen-Chieh Wang; Hsing-Pang Hsieh
Introduction: EGFR has been implicated in various malignancies such as NSCLC, breast, head and neck, and pancreatic cancer. Numerous drugs have been developed in order to target the tyrosine domain of EGFR as an approach in cancer treatment. Areas covered: This article focuses on the different generations of EGFR tyrosine kinase inhibitors (TKIs). This spans from the emergence of the first-generation EGFR-TKIs to overcoming drug resistance using second-generation EGFR-TKIs and to reducing adverse effect (AE) using mutant-selective third-generation EGFR-TKIs. Expert opinion: Current TKI treatment is frequently accompanied by drug resistance and/or serious AEs. There has been the promise of advancements in second-generation EGFR-TKIs that could overcome drug resistance, acting as second- or third-line salvage treatment, but this promise has yet to be met. That being said, both issues are currently being addressed with mutant-selective EGFR-TKIs with the expectation of bringing more EGFR-targeted therapy into the next phase of cancer therapy in the future.
Organic Letters | 2008
Hui-Yi Shiao; Hsing-Pang Hsieh; Chun-Chen Liao
The intramolecular Diels-Alder reaction of o-quinol allyl ether was accomplished and subsequently applied to the first total syntheses of natural products annuionone B (1) and both the proposed and revised structure of tanarifuranonol, 4 and 17.
Journal of Virology | 2011
Pi-Han Lin; Yi-Yu Ke; Chun-Ting Su; Hui-Yi Shiao; Hsing-Pang Hsieh; Yu-Kai Chao; Chun-Nan Lee; Chuan-Liang Kao; Yu-Sheng Chao; Sui-Yuan Chang
ABSTRACT The human immunodeficiency virus type 1 (HIV-1)-encoded RNA-binding protein Tat is known to play an essential role in viral gene expression. In the search for novel compounds to inhibit Tat transactivity, one coumarin derivative, BPRHIV001, was identified, with a 50% effective concentration (EC50) against HIV-1 at 1.3 nM. BPRHIV001 is likely to exert its effects at the stage after initiation of RNAPII elongation since Tat protein expression and the assembly of the Tat/P-TEFb complex remained unchanged. Next, a reduction of the p300 protein level, known to modulate Tat function through acetylation, was observed upon BPRHIV001 treatment, while the p300 mRNA level was unaffected. A concordant reduction of phosphorylated Akt, which was shown to be closely related to p300 stability, was observed in the presence of BPRHIV001 and was accompanied by a decrease of phosphorylated PDPK1, a well-known Akt activator. Furthermore, the docking analysis revealed that the reduced PDPK1 phosphorylation likely resulted from the allosteric effect of interaction between BPRHIV001 and PDPK1. With strong synergistic effects with current reverse transcriptase inhibitors, BPRHIV001 has the potential to become a promising lead compound for the development of a novel therapeutic agent against HIV-1 infection.
ChemMedChem | 2013
Yi-Yu Ke; Hui-Yi Shiao; Yung Chang Hsu; Chang-Ying Chu; Wen-Chieh Wang; Yen-Chun Lee; Wen-Hsing Lin; Chun-Hwa Chen; John T.-A. Hsu; Chun-Wei Chang; Cheng-Wei Lin; Teng-Kuang Yeh; Yu-Sheng Chao; Mohane Selvaraj Coumar; Hsing-Pang Hsieh
We describe the 3D‐QSAR‐assisted design of an Aurora kinase A inhibitor with improved physicochemical properties, in vitro activity, and in vivo pharmacokinetic profiles over those of the initial lead. Three different 3D‐QSAR models were built and validated by using a set of 66 pyrazole (Model I) and furanopyrimidine (Model II) compounds with IC50 values toward Aurora kinase A ranging from 33 nM to 10.5 μM. The best 3D‐QSAR model, Model III, constructed with 24 training set compounds from both series, showed robustness (r2CV=0.54 and 0.52 for CoMFA and CoMSIA, respectively) and superior predictive capacity for 42 test set compounds (R2pred=0.52 and 0.67, CoMFA and CoMSIA). Superimposition of CoMFA and CoMSIA Model III over the crystal structure of Aurora kinase A suggests the potential to improve the activity of the ligands by decreasing the steric clash with Val147 and Leu139 and by increasing hydrophobic contact with Leu139 and Gly216 residues in the solvent‐exposed region of the enzyme. Based on these suggestions, the rational redesign of furanopyrimidine 24 (clog P=7.41; Aurora A IC50=43 nM; HCT‐116 IC50=400 nM) led to the identification of quinazoline 67 (clog P=5.28; Aurora A IC50=25 nM; HCT‐116 IC50=23 nM). Rat in vivo pharmacokinetic studies showed that 67 has better systemic exposure after i.v. administration than 24, and holds potential for further development.
MedChemComm | 2014
Wen-Chieh Wang; Hui-Yi Shiao; Chieh‐Chien Lee; Ka-Shu Fung; Hsing-Pang Hsieh
Since the launch of Gleevec in 2001, several protein kinases have emerged as attractive therapeutic targets for the treatment of various cancers. One of these, anaplastic lymphoma kinase (ALK), has attracted a great deal of attention due to its oncogenic potential and essential role in the pathogenesis of a wide variety of human cancers, such as ALCLs, NSCLC, breast cancer, colorectal cancer, neuroblastoma, ovarian cancer, etc. To date, nine ALK inhibitors have entered clinical investigation for the treatment of cancers, including crizotinib, the first ALK inhibitor to be approved by the US FDA (in 2011) for the treatment of NSCLC patients. As resistance to crizotinib treatment has been reported in both preclinical and clinical settings, several second-generation ALK inhibitors to overcome both the wild-type and mutant ALK are being developed. In 2014, shortly after crizotinib was approved, the second-generation ALK inhibitor ceritinib was approved by the FDA. Biological activities of eight second-generation clinical ALK inhibitors are discussed in this review. Furthermore, the hit-to-drug evolution strategies used in the design of three ALK inhibitors – crizotinib, alectinib and ceritinib – are described in detail, to help medicinal chemists to understand and devise similar strategies to overcome lead development issues, such as potency, selectivity and metabolism, in the drug discovery projects.
PLOS ONE | 2011
Chun Hei Antonio Cheung; Wen-Hsing Lin; John T.-A. Hsu; Tzyh-Chyuan Hour; Teng-Kuang Yeh; Shengkai Ko; Tzu-Wen Lien; Mohane Selvaraj Coumar; Jin-Fen Liu; Wen-Yang Lai; Hui-Yi Shiao; Tian-Ren Lee; Hsing-Pang Hsieh; Jang Yang Chang
Background Over-expression of Aurora kinases promotes the tumorigenesis of cells. The aim of this study was to determine the preclinical profile of a novel pan-Aurora kinase inhibitor, BPR1K653, as a candidate for anti-cancer therapy. Since expression of the drug efflux pump, MDR1, reduces the effectiveness of various chemotherapeutic compounds in human cancers, this study also aimed to determine whether the potency of BPR1K653 could be affected by the expression of MDR1 in cancer cells. Principal Findings BPR1K653 specifically inhibited the activity of Aurora-A and Aurora-B kinase at low nano-molar concentrations in vitro. Anti-proliferative activity of BPR1K653 was evaluated in various human cancer cell lines. Results of the clonogenic assay showed that BPR1K653 was potent in targeting a variety of cancer cell lines regardless of the tissue origin, p53 status, or expression of MDR1. At the cellular level, BPR1K653 induced endo-replication and subsequent apoptosis in both MDR1-negative and MDR1-positive cancer cells. Importantly, it showed potent activity against the growth of xenograft tumors of the human cervical carcinoma KB and KB-derived MDR1-positive KB-VIN10 cells in nude mice. Finally, BPR1K653 also exhibited favorable pharmacokinetic properties in rats. Conclusions and Significance BPR1K653 is a novel potent anti-cancer compound, and its potency is not affected by the expression of the multiple drug resistant protein, MDR1, in cancer cells. Therefore, BPR1K653 is a promising anti-cancer compound that has potential for the management of various malignancies, particularly for patients with MDR1-related drug resistance after prolonged chemotherapeutic treatments.
ChemMedChem | 2010
Yi-Hui Peng; Mohane Selvaraj Coumar; Jiun-Shyang Leou; Jian-Sung Wu; Hui-Yi Shiao; Chia-Hui Lin; Wen-Hsing Lin; Tzu Wen Lien; Xin Chen; John T.-A. Hsu; Yu-Sheng Chao; Chien-Fu Huang; Ping-Chiang Lyu; Hsing-Pang Hsieh; Su-Ying Wu
The need to develop safer and more effective antidiabetic drugs is essential owing to the growth worldwide of the diabetic population. Targeting the PPAR receptor is one strategy for the treatment of diabetes; the PPAR agonists rosiglitazone and pioglitazone are already on the market. Here we report the identification of a potent PPAR agonist, 15, whose PPARγ activation was more than 20 times better than that of rosiglitazone. Compound 15 was designed to incorporate an indole head with a carboxylic acid group, and 4‐phenylbenzophenone tail to achieve a PPARγ EC50 of 10 nM. Compound 15 showed the most potent PPARγ agonist activity among the compounds we investigated. To gain molecular insight into the improved potency of 15, a structural biology study and binding energy calculations were carried out. Superimposition of the X‐ray structures of 15 and agonist 10 revealed that, even though they have the same indole head part, they adopt different conformations. The head part of 15 showed stronger interactions toward PPARγ; this could be due to the presence of the novel tail part 4‐phenylbenzophenone, which could enhance the binding efficiency of 15 to PPARγ.
ChemMedChem | 2012
Jiann-Yih Yeh; Mohane Selvaraj Coumar; Hui-Yi Shiao; Ta-Jen Lin; Yen-Chun Lee; Hui-Chen Hung; Shengkai Ko; Fu-Ming Kuo; Ming-Yu Fang; Yu-Lin Huang; John T.-A. Hsu; Teng-Kuang Yeh; Shin-Ru Shih; Yu-Sheng Chao; Jim-Tong Horng; Hsing-Pang Hsieh
From a high-throughput screening (HTS) hit with inhibitory activity against virus-induced cytophathic in the low micromolar range, we have developed a potent anti-influenza lead through careful optimization without compromising the drug-like properties of the compound. An orally bioavailable compound was identified as a lead agent with nanomolar activity against influenza, representing a 140-fold improvement over the initial hit.
Journal of Biomolecular Structure & Dynamics | 2017
Vivek Kumar Singh; Hsin-Huei Chang; Ching-Chuan Kuo; Hui-Yi Shiao; Hsing-Pang Hsieh; Mohane Selvaraj Coumar
Chronic myeloid leukemia (CML) is caused by chromosomal rearrangement resulting in the expression of Bcr-Abl fusion protein with deregulated Abl tyrosine kinase activity. Approved drugs – imatinib, dasatinib, nilotinib, and ponatinib – target the ATP-binding site of Abl kinase. Even though these drugs are initially effective, long-term usefulness is limited by the development of resistance. To overcome this problem, targeting the allosteric site of Abl kinase, which is remote from the ATP-binding site is found to be a useful strategy. In this study, structure-based and ligand-based virtual screening methods were applied to narrow down possible drugs (from DrugBank database) that could target the allosteric site of Abl kinase. Detailed investigations of the selected drugs in the allosteric site of Abl kinase, using molecular dynamics and steered molecular dynamics simulation shows that gefitinib, an EGFR inhibitor approved for the treatment of lung cancer, could bind effectively to the allosteric site of Bcr-Abl. More interestingly, gefitinib was found to enhance the ability of imatinib to bind at the ATP-binding site of Bcr-Abl kinase. Based on the in silico findings, gefitinib was tested in combination with imatinib in K562 CML cell line using MTT cell proliferation assay and found to have a synergistic antiproliferative activity. Further detailed mechanistic study could help to unravel the full potential of imatinib – gefitinib combination for the treatment of CML.