http://chineseinput.net/에서 pinyin(병음)방식으로 중국어를 변환할 수 있습니다.
변환된 중국어를 복사하여 사용하시면 됩니다.
Prediction of Relative Stability between TACE/Gelastatin and TACE/Gelastatin Hydroxamate
남기엽,한균희,김환묵,노경태 대한화학회 2010 Bulletin of the Korean Chemical Society Vol.31 No.11
A gelastatins (1), natural MMP inhibitors, and their hydroxamate analogues (2) in TACE enzyme evaluated for discovery of potent TACE inhibitors. We have employed molecular dynamics simulations to compute the relative free energy of hydration and binding to TACE for gelastatin (1) and its hydroxamate analogue (2). The relative free energy difference is directly described in this article using the free energy perturbation approach as a means to accurately predict the TACE inhibitor of gelastatin analogues. The results show that the good agreement between the experimental and theoretical relative free energies of binding, gelastatin hydroxamate (2) binds stronger to TACE by ‒3.37 kcal/mol. The desolvation energy costs significantly reduced binding affinity, hydroxamate group associated with high desolvation energy formed strong favorable interactions with TACE with more than compensated for the solvation costs and therefore led to an improvement in relative binding affinity.
Identification of a thienopyrimidine derivatives target by a kinome and chemical biology approach
이철호,양지선,한균희 대한약학회 2015 Archives of Pharmacal Research Vol.38 No.9
Target identification through chemical biologyhas been considered one of the most efficient approachesfor drug discovery. Thienopyrimidine derivatives weredesigned to discover potent IjB kinase b (IKKb) inhibitorsbased on a known IKKb inhibitor library. Most of thethienopyrimidine derivatives inhibited nitric oxide andtumor necrosis factor alpha, which are downstream of theNF-jB signaling pathway, but not IKKb. To identify theappropriate targets of thienopyrimidine analogues, chemicalbiology approaches, including text mining and a subsequentkinase panel assay from the kinome profiling wereused. Based on the results, Fms-like tyrosine kinase 3 wasfound to be the target for thienopyrimidine derivatives, andwas confirmed to be a potent inhibitor for acute myeloidleukemia.
황정하,차부현,한균희,최강열,민도식,Tran The Bach 생화학분자생물학회 2015 Experimental and molecular medicine Vol.47 No.-
The Wnt/β-catenin pathway has a role in osteoblast differentiation and bone formation. We screened 100 plant extracts and identified an extract from Euodia sutchuenensis Dode (ESD) leaf and young branch as an effective activator of the Wnt/β-cateninpathway. ESD extract increased β-catenin levels and β-catenin nuclear accumulation in murine primary osteoblasts. The ESD extract also increased mRNA levels of osteoblast markers, including RUNX2, BMP2 and COL1A1, and enhanced alkaline phosphatase (ALP) activity in murine primary osteoblasts. Both ESD extract-induced β-catenin increment and ALP activation were abolished by β-catenin knockdown, confirming that the nt/β-catenin pathway functions in osteoblast differentiation. ESD extract enhanced terminal osteoblast differentiation as shown by staining with Alizarin Red S and significantly increased murine calvarial bone thickness. This study shows that ESD extract stimulates osteoblast differentiation via the Wnt/β-catenin pathway and enhances murine calvarial bone formation ex vivo.
이상훈,김은영,한정민,한균희,장윤수 대한암학회 2023 Cancer Research and Treatment Vol.55 No.3
Purpose The mammalian target of rapamycin complex 1 (mTORC1) regulates cell growth and proliferation by growth factor coordination and amino acid availability. Leucyl-tRNA synthetase 1 (LARS1) senses the intracellular leucine concentration and mediates amino acid-induced activation of mTORC1. Thus, LARS1 inhibition could be useful in cancer treatment. However, the fact that mTORC1 can be stimulated by various growth factors and amino acids suggests that LARS1 inhibition alone has limitations in inhibiting cell growth and proliferation. We investigated the combined effects of BC-LI-0186, a LARS1 inhibitor, and trametinib, an MEK inhibitor, on non–small cell lung cancer (NSCLC). Materials and Methods Protein expression and phosphorylation were observed by immunoblotting, and genes differentially expressed between BC-LI-0186–sensitive and –resistant cells were identified by RNA sequencing. The combined effect of the two drugs was inferred from the combination index values and a xenograft model. Results LARS1 expression was positively correlated with mTORC1 in NSCLC cell lines. BC-LI-0186 treatment of A549 and H460 cells maintained in media supplemented with fetal bovine serum revealed paradoxical phosphorylation of S6 and activation of mitogen- activated protein kinase (MAPK) signaling. Compared with BC-LI-0186–sensitive cells, –resistant cells showed enrichment of the MAPK gene set. The combination of trametinib and BC-LI-0186 inhibited the phosphorylation of S6, MEK, and extracellular signal-regulated kinase and their synergistic effects were confirmed in a mouse xenograft model. Conclusion The combination of BC-LI-0186 and trametinib inhibited the non-canonical mTORC1-activating function of LARS1. Our study demonstrated a new therapeutic approach for NSCLC without targetable driver mutations.
이상규,조용희,차부현,윤정수,노은지,정우정,박지은,김현태,김태일,민도식,한균희,최강열 생화학분자생물학회 2018 Experimental and molecular medicine Vol.50 No.-
Drugs targeting the epidermal growth factor receptor (EGFR), such as cetuximab and panitumumab, have been prescribed for metastatic colorectal cancer (CRC), but patients harboring KRAS mutations are insensitive to them and do not have an alternative drug to overcome the problem. The levels of β-catenin, EGFR, and RAS, especially mutant KRAS, are increased in CRC patient tissues due to mutations of adenomatous polyposis coli (APC), which occur in 90% of human CRCs. The increases in these proteins by APC loss synergistically promote tumorigenesis. Therefore, we tested KYA1797K, a recently identified small molecule that degrades both β-catenin and Ras via GSK3β activation, and its capability to suppress the cetuximab resistance of KRAS-mutated CRC cells. KYA1797K suppressed the growth of tumor xenografts induced by CRC cells as well as tumor organoids derived from CRC patients having both APC and KRAS mutations. Lowering the levels of both β-catenin and RAS as well as EGFR via targeting the Wnt/β-catenin pathway is a therapeutic strategy for controlling CRC and other types of cancer with aberrantly activated the Wnt/β-catenin and EGFR-RAS pathways, including those with resistance to EGFR-targeting drugs attributed to KRAS mutations.
최용석,박성규,김환묵,강종순,Yeo Dae Yoon,한상배,한정환,양지선,한균희 생화학분자생물학회 2008 Experimental and molecular medicine Vol.40 No.5
In light of the anti-inflammatory properties of histone deacetylase (HDAC) inhibitors, such as suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA), we examined a new HDAC inhibitor KBH-A42 for its anti-inflammatory activities. KBH-A42 showed noteworthy anti-inflammatory properties in vitro via suppression of the production of TNF-α, a proinflammatory cytokine, and nitric oxide (NO), a proinflammatory effector molecule, in LPS-stimulated RAW264.7 cells and peritoneal macrophages. It also inhibited TNF-α production in vivo as demonstrated in a LPS-induced mouse endotoxemia model. The levels of TNF-α, IL-1β, IL-6 and iNOS mRNAs determined by RT-PCR propose that the inhibition of these pro-inflammatory mediators by KBH-A42 resulted from inhibiting expression of these genes. However, the EMSA study to see the effect of KBH-A42 on the binding of NF-κB, a transcription factor, to a specific DNA sequence showed that the binding of NF-κB to DNA was not changed regardless of increasing the concentration of KBH-A42 in the presence and absence of LPS stimulation. Interestingly, DNA binding of another transcription factor AP-1 dose-dependently increased by KBH-A42. KBH-A42 differentially regulated the phosphorylation of MAP kinases. While the phosphprylation of ERK1/2 and SAPK/JNK was not affected by KBH-A42, the phosphorylation of p38 decreased by KBH-A42. These results showed that KBH-A42 inhibits production of proinflammatory cytokines in macrophages by decreasing their mRNA levels, and p38 kinase is involved in the KBH-A42-mediated inhibition.
Inhibition of Human Ovarian Tumor Growth by Cytokine-induced Killer Cells
김환묵,강종순,임재승,박성규,이기호,윤여대,이창우,이기훈,한균희,양규환,김연진,김영수,한상배 대한약학회 2007 Archives of Pharmacal Research Vol.30 No.11
Despite the recent improvement in the treatment of ovarian cancer, this disease is still leading cause of cancer death in women. In this study, the anti-tumor activity of cytokine-induced killer (CIK) cells against human ovarian cancer was evaluated in vitro and in vivo. Although CD3+CD56+ cells were rare in fresh human peripheral blood mononuclear cells, they could expand more than 1,000-fold on day 14 in the presence of anti-CD3 antibody plus IL-2. At an effector-target cell ratio of 30:1, CIK cells destroyed 45% of SK-OV-3 human ovarian cancer cells, which was determined by the 51Cr-release assay. In addition, CIK cells at a dose of 23 million cells per mouse inhibited 73% of SK-OV-3 tumor growth in nude mouse xenograft assay. This study suggests that CIK cells may be used as an adoptive immunotherapy for patients with ovarian cancer.
Yeojin Sung,Seungbin Cha,Sang Bum Kim,Hakhyun Kim,Seonghwi Choi,Sejin Oh,Minseo Kim,Yunji Lee,Gino Kwon,Jooyoung Lee,Joo-Youn Lee,한균희,김현석 생화학분자생물학회 2022 BMB Reports Vol.55 No.12
Epithelial-to-mesenchymal transition (EMT)-subtype gastric cancershave the worst prognosis due to their higher recurrence rate,higher probability of developing metastases and higher chemoresistancecompared to those of other molecular subtypes. Pharmacologicallyactionable somatic mutations are rarely found inEMT-subtype gastric cancers, limiting the utility of targeted therapies. Here, we conducted a high-throughput chemical screenusing 37 gastric cancer cell lines and 48,467 synthetic smallmoleculecompounds. We identified YK-135, a small-moleculecompound that showed higher cytotoxicity toward EMT-subtypegastric cancer cell lines than toward non-EMT-subtype gastriccancer cell lines. YK-135 exerts its cytotoxic effects by inhibitingmitochondrial complex I activity and inducing AMP-activatedprotein kinase (AMPK)-mediated apoptosis. We found that thelower glycolytic capacity of the EMT-subtype gastric cancer cellsconfers synthetic lethality to the inhibition of mitochondrialcomplex I, possibly by failing to maintain energy homeostasis. Other well-known mitochondrial complex I inhibitors (e.g., rotenoneand phenformin) mimic the efficacy of YK-135, supportingour results. These findings highlight mitochondrial complex Iinhibitors as promising therapeutic agents for EMT-subtype gastriccancers and YK-135 as a novel chemical scaffold for further drugdevelopment.