YOUAI Co.

Suigen, South Korea

YOUAI Co.

Suigen, South Korea
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Screening V.,YOUAI Co. | Kim N.D.,YOUAI Co. | Lee Y.,YOUAI Co. | Ahn S.K.,Incheon National University
Bulletin of the Korean Chemical Society | Year: 2012

The 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme is involved in modulation of glucocorticoid activity within target tissues. This enzyme may contribute to obesity and/or metabolic disease through its action in adipose or liver tissue. Inhibition of 11β-HSD1 has major therapeutic potential for glucocorticoidassociated diseases, including obesity, diabetes (wound healing), and muscle atrophy. To develop such therapeutics, we performed a pharmacophore-based virtual screening (VS) for identification of novel 11β-HSD1 inhibitors and found that the VS hit compounds show potent inhibition of 11β-HSD1 enzyme activity. Further, we present a binding model for active compounds. The proposed pharmacophore may serve as a useful guideline for future design of new chemical entities as 11β-HSD1-targeted antidiabetic agents.


Ahn J.-H.,Incheon National University | Ahn S.K.,Incheon National University | Ahn S.K.,YOUAI Co. | Lee M.,Incheon National University
Biochemical and Biophysical Research Communications | Year: 2012

In human cancers, B-Raf is the most frequently mutated protein kinase in the MAPK signaling cascade, making it an important therapeutic target. We recently discovered a potent and selective B-Raf inhibitor, UI-152, by using a structure-based drug design strategy. In this study, we examined whether B-Raf inhibition by UI-152 may be an effective therapeutic strategy for eliminating cancer cells transformed with v-Ha- ras (Ras-NIH 3T3). UI-152 displayed selective cytotoxicity toward Ras-NIH 3T3 cells while having little to no effect on non-transformed NIH 3T3 cells. We found that treatment with UI-152 markedly increased autophagy and, to a lesser extent, apoptosis. However, inhibition of autophagy by addition of 3-MA failed to reverse the cytotoxic effects of UI-152 on Ras-NIH 3T3 cells, demonstrating that apoptosis and autophagy can act as cooperative partners to induce growth inhibition in Ras-NIH 3T3 cells treated with UI-152. Most interestingly, cell responses to UI-152 appear to be paradoxical. Here, we showed that although UI-152 inhibited ERK, it induced B-Raf binding to Raf-1 as well as Raf-1 activation. This paradoxical activation of Raf-1 by UI-152 is likely to be coupled with the inhibition of the mTOR pathway, an intracellular signaling pathway involved in autophagy. We also showed for the first time that, in multi-drug resistant cells, the combination of UI-152 with verapamil significantly decreased cell proliferation and increased autophagy. Thus, our findings suggest that the inhibition of autophagy, in combination with UI-152, offers a more effective therapeutic strategy for v-Ha- ras-transformed cells harboring wild-type B-Raf. © 2011 Elsevier Inc.


Ahn J.-H.,Incheon National University | Lee Y.W.,Virginia Polytechnic Institute and State University | Ahn S.K.,Incheon National University | Ahn S.K.,YOUAI Co. | Lee M.,Incheon National University
Life Sciences | Year: 2014

Aims An activating mutation of BRAF (BRAF-V600E) has been reported in a subset of malignant brain tumors. Thus, the aim of the present study was to identify the antiproliferative effect of the new oncogenic B-Raf targeting drug UAI-201 on 6 types of glioma cell lines with differing B-Raf mutational status. Main methods The IC50 values of UAI-201 were determined using crystal violet assays in six glioma cell lines. Real-time RT-PCR was performed to assess the functional role of multidrug resistance proteins in response to UAI-201. The effects of UAI-201 on six glioma cells were further examined by immunoblotting analysis, cell cycle analysis, flow cytometric apoptotic assay and autophagy assay. To identify the role of autophagy in UAI-201-induced growth inhibition, Atg5 and Beclin 1 were knocked down by RNA interference. Key findings Real-time RT-PCR analysis showed a poor correlation between UAI-201 activity and the expression level of multidrug resistance proteins. The growth inhibitory effects of UAI-201 correlated with the BRAF-V600E genotype of the glioma cell lines. BRAF blockade with UAI-201 resulted in dose-dependent inhibition of MEK/ERK phosphorylations and increased G0/G1 arrest in glioma cells with BRAF-V600E. Interestingly, UAI-201 preferentially induced autophagy in BRAF-V600E cells, but not in BRAF-WT cells. More notably, autophagy inhibition through siRNA-mediated Beclin 1 knockdown partially attenuated the growth inhibition induced by UAI-201 in BRAF-V600E cells. Significance The pro-death autophagic processes could be one of the underlying mechanisms for the sensitization of BRAF-V600E glioma cells toward UAI-201. © 2014 Elsevier Inc.


Nam K.-Y.,Youai Co. | Choi N.S.,Youai Co. | Han C.K.,Youai Co. | Ahn S.K.,Incheon National University
Bioorganic and Medicinal Chemistry Letters | Year: 2012

Chalcones have an affinity for many receptors, enzymes, and transcription factors as flavonoid analogues. Their most studied pharmacological action is that of vasodilatation due to inhibition of phosphodiesterase 5A1 (PDE5A1). To this end, we have established a recursive partitioning model with 3 chemical descriptors for the prediction of compounds that can inhibit PDE5A1. This model was able to predict active compounds with an accuracy of 82.8%. Compound 4 was found to be a potent and selective inhibitor, with a relatively low IC 50 value. The binding mechanism of this compound was also investigated through molecular docking studies. © 2012 Elsevier Ltd. All rights reserved.


Kim Y.-K.,Incheon National University | Ahn S.K.,Incheon National University | Ahn S.K.,YOUAI Co. | Lee M.,Incheon National University
Cancer Letters | Year: 2012

Activating mutations in B-Raf kinase are common in malignant melanoma, an aggressive tumor of neuroectodermal origin. In the present study, the antiproliferative effect of the new oncogenic B-Raf targeting drug UI-152 on two types of melanoma cell lines with differing B-Raf mutational status was examined, and the underlying mechanisms were investigated. In cellular assays, UI-152 displayed high selectivity for tumor cells bearing B-Raf(V600E), showing more than 1000-fold higher inhibition of their proliferation than wild-type B-Raf-bearing cells. As expected, UI-152 completely abolished MEK-ERK phosphorylation in A375P cells harboring B-Raf(V600E). In SK-MEL-2 cells expressing B-Raf(WT), UI-152 caused the paradoxical activation of the MAPK pathway but to a much lesser extent than that observed of other oncogenic B-Raf inhibitors. These data suggest that UI-152 may be a more ideal B-Raf inhibitor capable of preserving potency against oncogenic B-Raf while minimizing the paradoxical activation of MAPK signaling. In addition, we showed that UI-152 treatment of A375P cells simultaneously induced cellular autophagy and apoptosis. However, autophagy inhibition with 3-methyladenine and inhibition of apoptosis by overexpression of the X-linked inhibitor of apoptosis failed to rescue melanoma cells from UI-152-induced cell death, implying that apoptosis and autophagy may cooperate in the induction of cell death in UI-152-treated cells. Collectively, our data suggest that UI-152 may be an effective B-Raf inhibitor and a potential therapeutic strategy for B-Raf(WT) and Ras mutant melanoma. © 2012 Elsevier Ireland Ltd.


Joung J.Y.,Bioinformatics and Molecular Design Research Center | Joung J.Y.,Yonsei University | Kim H.,Yonsei University | Kim H.M.,Gachon University | And 3 more authors.
Bulletin of the Korean Chemical Society | Year: 2012

P-gp (P-glycoprotein) is a member of the ATP binding cassette (ABC) family of transporters. It transports many kinds of anticancer drugs out of the cell. It plays a major role as a cause of multidrug resistance (MDR). MDR function may be a cause of the failure of chemotherapy in cancer and influence pharmacokinetic properties of many drugs. Hence classification of candidate drugs as substrates or nonsubstrate of the P-gp is important in drug development. Therefore to identify whether a compound is a P-gp substrate or not, in silico method is promising. Recursive Partitioning (RP) method was explored for prediction of P-gp substrate. A set of 261 compounds, including 146 substrates and 115 nonsubstrates of P-gp, was used to training and validation. Using molecular descriptors that we can interpret their own meaning, we have established two models for prediction of P-gp substrates. In the first model, we chose only 6 descriptors which have simple physical meaning. In the training set, the overall predictability of our model is 78.95%. In case of test set, overall predictability is 69.23%. Second model with 2D and 3D descriptors shows a little better predictability (overall predictability of training set is 79.29%, test set is 79.37%), the second model with 2D and 3D descriptors shows better discriminating power than first model with only 2D descriptors. This approach will be used to reduce the number of compounds required to be run in the P-gp efflux assay.


Eum K.-H.,Incheon National University | Eum K.-H.,YOUAI Co. | Ahn S.K.,Incheon National University | Ahn S.K.,YOUAI Co. | And 2 more authors.
Molecular and Cellular Biochemistry | Year: 2013

B-Raf is the most frequently mutated protein kinase in the MAPK signaling cascade in human cancers, making it an important therapeutic target. Here, we describe the differential effects of two Raf-targeting drugs, sorafenib and PLX4720, on multidrug-resistant v-Ha-ras-transformed cells (Ras-NIH 3T3/Mdr). We demonstrate that the growth of the NIH 3T3/Mdr cell line was affected in a dose-dependent manner more significantly by the pan-Raf inhibitor sorafenib than by the selective mutant B-Raf inhibitor PLX4720. Despite their differential effects on LKB1/AMPK phosphorylation, both sorafenib and PLX4720 inhibited downstream mTOR signaling with concomitant induction of autophagy, implying that the differential effects of sorafenib and PLX4720 on multidrug-resistant cells might not be due to different levels of autophagy and apoptosis. Interestingly, sorafenib caused a dose-dependent increase in rhodamine 123 uptake and retention. More importantly, sorafenib reversed the resistance to paclitaxel in Ras-NIH 3T3/Mdr cells. Moreover, MEK/ERK signaling was hyperactivated by the selective mutant B-Raf inhibitor PLX4720 and inhibited by the pan-Raf inhibitor sorafenib. Our data suggest that sorafenib sensitivity in MDR cells is mediated through the inhibition of P-glycoprotein activity following strong inhibition of Raf/MEK/ERK signaling. Thus, Raf inhibition with sorafenib might be a promising approach to abrogate the multidrug resistance of cancer cells. © 2012 Springer Science+Business Media, LLC.


A novel purinylpyridinylamino-2,4-difluorophenyl sulfonamide derivative, a pharmaceutically acceptable salt thereof, a preparation method thereof, and a pharmaceutical composition with an inhibitory activity against Raf kinase, containing the same as an active ingredient are provided. The purinylpyridinylamino-2,4-difluorophenyl sulfonamide derivative of the present invention effectively regulates the activity of B-Raf kinase, and thus may be useful for preventing or treating cancers induced by the over-activation of Raf kinase, especially various melanoma, colorectal cancer, prostate cancer, thyroid cancer, ovarian cancer and the like.


A novel purinylpyridinylamino-2,4-difluorophenyl sulfonamide derivative, a pharmaceutically acceptable salt thereof, a preparation method thereof, and a pharmaceutical composition with an inhibitory activity against Raf kinase, containing the same as an active ingredient are provided. The purinylpyridinylamino-2,4-difluorophenyl sulfonamide derivative of the present invention effectively regulates the activity of B-Raf kinase, and thus may be useful for preventing or treating cancers induced by the over-activation of Raf kinase, especially various melanoma, colorectal cancer, prostate cancer, thyroid cancer, ovarian cancer and the like.


PubMed | Youai Co.
Type: Journal Article | Journal: Bioorganic & medicinal chemistry letters | Year: 2012

Chalcones have an affinity for many receptors, enzymes, and transcription factors as flavonoid analogues. Their most studied pharmacological action is that of vasodilatation due to inhibition of phosphodiesterase 5A1 (PDE5A1). To this end, we have established a recursive partitioning model with 3 chemical descriptors for the prediction of compounds that can inhibit PDE5A1. This model was able to predict active compounds with an accuracy of 82.8%. Compound 4 was found to be a potent and selective inhibitor, with a relatively low IC(50) value. The binding mechanism of this compound was also investigated through molecular docking studies.

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