Sunkyung Lee

Korea Research Institute of Chemical Technology · Division of Drug Discovery Research

Direct inhibitors of glycogen synthase kinase 3β (GSK3β) have been investigated and reported for the past 20 years. In the search for novel scaffold inhibitors, 3000 compounds were selected through structure-based virtual screening (SBVS), and then high-throughput enzyme screening was performed. Among the active hit compounds, pyrazolo [1,5-a]pyrim...

Recent development of the chemical inhibitors specific to oncogenic KRAS (Kirsten Rat Sarcoma 2 Viral Oncogene Homolog) mutants revives much interest to control KRAS-driven cancers. Here, we report that AIMP2-DX2, a variant of the tumor suppressor AIMP2 (aminoacyl-tRNA synthetase-interacting multi-functional protein 2), acts as a cancer-specific re...

Although protein-protein interactions (PPIs) have emerged as an attractive therapeutic target space, the identification of chemicals that effectively inhibit PPIs remains challenging. Here, we identified through library screening a chemical probe, compound 1 that can inhibit the tumor-promoting interaction between the oncogenic factor AIMP2-DX2 and...

While aminoacyl-tRNA synthetase-interacting multifunctional protein 2 (AIMP2) is a tumor suppressor, its exon 2-depleted splice variant (AIMP2-DX2 or shortly DX2) is highly expressed in human lung cancer, and the ratio of DX2 to AIMP2 increases according to the progression of lung cancer. In this study, pyrimethamine inhibited the level of DX2 (IC5...

In a previous study, we showed that several octahydroindene derivatives are potent protease activated receptor 1 (PAR1) antagonists. In the current study, we prepared a series of trans‐fused 5,5‐difulorooctahydroindenes which do not have a C5 stereogenic center, and evaluated their biological activities and metabolic stabilities. Compound 19 in thi...

Maternal embryonic leucine zipper kinase (MELK) has been implicated in various cellular processes and is highly upregulated in diverse cancers, then it is thought to be a promising anticancer target. 3-Anilino-1H-pyrazolo[3,4-b]pyridine scaffold was identified as a novel scaffold for MELK kinase inhibitors in high throughput screening (HTS). From e...

Protease activated receptor 1 (PAR1) has been considered as a promising antiplatelet target to prevent thrombotic cardiovascular events in patients with prior myocardial infarction or peripheral arterial diseases. Previously, we found a series of octahydroindene analogues to have high potency on PAR1 and no significant cytotoxicity but poor metabol...

Protease activated receptor 1 (PAR1) has been considered as a promising antiplatelet target to prevent thrombotic cardiovascular events in patients with prior myocardial infarction or peripheral arterial diseases. Previously, we found a series of octahydroindene analogues to have high potency on PAR1 and no significant cytotoxicity but poor metabol...

Even though nicotinic acid (niacin) appears to have beneficial effects on human lipid profiles, niacin-induced cutaneous vasodilatation called flushing limits its remedy to patient. GPR109A is activated by niacin and mediates the anti-lipolytic effects. Based on the hypothesis that β-arrestin signaling mediates niacin-induced flushing, but not its...

Octahydroindene was identified as a novel scaffold for protease activated receptor 1 (PAR1) antagonists. Herein, the 2-position (C2) was explored for structure-activity relationship (SAR) studies. Compounds 14, 19, and 23b showed IC50 values of 1.3, 8.6, and 2.7 nM in a PAR1 radioligand binding assay, respectively, and their inhibitory activities o...

Aminoacyl-tRNA synthetase-interacting multifunctional protein 2 (AIMP2) is a potent tumor suppressor, that induces apoptosis in response to various oncogenic signals. AIMP2-DX2, an exon2-deleted splicing variant of AIMP2, is up-regulated in lung cancer and competitively suppresses the pro-apoptotic activity of AIMP2, resulting in tumorigenesis. Her...

B cell-activating factor (BAFF) is a key regulator of B lymphocyte development. Signals from BAFF are transmitted through binding to a specific BAFF receptor (BAFF-R). Here, we established screening method to find a specific inhibitor for the interference of BAFF-BAFF-R interactions. We screened oxazole-4-carbonylguanidine derivatives and selected...

B cell-activating factor (BAFF) transmitted signals through binding to specific BAFF receptors (BAFF-R) to regulate B cell survival and development. We used MTT assay to examine the cytotoxicity of chemicals, flow cytometry analysis to measure BAFF-BAFF-R interactions, and western blotting to detect BAFF protein. Here, we established screening meth...

Antiplatelet therapy is a key treatment in atherothrombotic disease and platelet is activated via multiple pathways. Current agents do not interfere with all pathways including the protease-activated receptor-1 (PAR-1) pathway stimulated by thrombin. New antiplatelet agents targeting PAR-1 are aimed to reduce thrombosis ideally without increasing b...

Caspase 3, a member of cysteine protease family, is well known as a major apoptosis effector and is involved in cell death as a result of ischemic diseases such as stroke and myocardial infarction, therefore the inhibition of caspase 3 may protect those apoptotic cell damages. During the high-throughput screening of the compounds from the Korea Che...

To identify a non-acylguanidine NHE-1 inhibitor, an acylguanidne group was replaced with an imidazole group in the potent NHE-1 inhibitors with furan or benzothiphene core template, found from our previous studies. We synthesized and biologically evaluated 4-heteroaryl-2-amino-5-methylimidazole derivatives. All those imidazole compounds (16-18) rep...

A series of (2-aryl-5-methylimidazol-4-ylcarbonyl)guanidines and (2-aryl-5-methyloxazol-4-ylcarbonyl)guanidines were synthesized and evaluated as NHE-1 inhibitors. The structure-activity relationships well matched those of furan derivatives, which were previously investigated. The (2,5-disubstituted)phenyl compounds showed better activities than th...

We investigated the effects of a novel Na+/H+ exchanger-1 (NHE-1) inhibitor KR-33028 on glutamate excitotoxicity in cultured neuron cells in vitro and cerebral infarct in vivo by comparing its potency with that of zoniporide, a well-known, highly potent NHE-1 inhibitor. KR-33028 inhibited NHE-1 activation in a concentration-dependent manner (IC50=2...

Blocking of poly(ADP-ribose) polymerase (PARP)-1 has been expected to protect the heart from ischemia-reperfusion injury. We have recently identified a novel and orally active PARP-1 inhibitor, KR-33889 [2-[methoxycarbonyl(4-methoxyphenyl)-methylsulfanyl]-1H-benzimidazole-4-carboxylic acid amide], and its major metabolite, KR-34285 [2-[carboxy(4-me...

The present study was performed to evaluate the cardioprotective effects of KR-33028, a novel Na+/H+ exchanger subtype 1 (NHE-1) inhibitor, in rat and dog models of coronary artery occlusion and reperfusion. In anesthetized rats subjected to a 45-min coronary occlusion and a 90-min reperfusion, KR-33028 at 5 min before occlusion (i.v. bolus) dose-d...

The C-3 substituents effect on NHE-1 inhibitory activity of (5-arylfuran-2-ylcarbonyl)guanidines, previously identified as potent NHE-1 inhibitors, was investigated. The introduction of amine or alkyl groups at the 3-position of the furan ring, next to the acylguanidine moiety, remarkably improves NHE-1 inhibitory potency. Especially the important...

We evaluated the cardioprotective effects of 4-cyano (benzo[b]thiophene-2-carbonyl)guanidine (KR-33028), a recently developed inhibitor of the Na+/H+ exchanger (NHE), on hypoxia-induced H9c2 cell death and on perfused rat hearts subjected to ischemia/reperfusion. KR-33028 inhibited in a concentration-dependent manner the recovery from acidosis indu...

In this study, we investigated whether a novel anti-ischemic KATP opener KR-31378 [(2S,3S,4R)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methly-2-dimethoxymethly-2H-benzopyran-4-yl)-N'-benzylguanidine] has protective effect against oxidative stress-induced death in heart-derived H9c2 cells. Cell death was induced by BSO, butionine sulfoximine, whi...

Poly(ADP-ribose) polymerase (PARP) plays a pivotal role in the repair of DNA strand breaks. However, excessive activation of PARP causes a rapid depletion of intracellular energy, leading to cell death. PARP inhibitors may have potential therapeutic benefit in the treatment of myocardial ischemia, stroke, and neurodegenerative disease. With these e...

KR-33028 (N-[4-cyano-benzo[b]thiophene-2-carbonyl]guanidine) is a new cardioprotective agent for preventing ischemia-reperfusion injury. This study was performed to identify the metabolic pathway of KR-33028 in human liver microsomes and to compare its metabolism with that of cryopreserved human hepatocytes. Human liver microsomal incubation of KR-...

A novel Na+/H+ exchanger-1 (NHE-1) inhibitor [5-(2-methoxy-5-chloro-5-phenyl)furan-2-ylcarbonyl]guanidine (KR-32570) has been previously demonstrated to elicit cardioprotective effect against ischemic injury in rat heart. In the present study, we examined the effects of KR-32570 on cell death induced by hypoxic insult in heart-derived H9c2 cells. T...

We investigated the effects of an Na(+)/H(+) exchanger inhibitor, sabiporide, on excitotoxicity in cultured neuronal cells and in vivo. Sabiporide attenuated glutamate- or NMDA (N-methyl-d-aspartic acid)-induced neuronal cell death. Sabiporide also reduced glutamate or NMDA-induced increase in [Ca(2+)](i). In in vivo brain ischemia model, sabiporid...

The present study was performed to evaluate the cardioprotective effects of [5-(2-methoxy-5-chloro-5-phenyl)furan-2-ylcarbonyl]guanidine (KR-32570) in rat and dog models of coronary artery occlusion and reperfusion. In addition, we sought to clarify the efficacy of KR-32570 on reperfusion-induced fatal ventricular arrhythmia. In anesthetized rats s...

We attempted to replace a benzopyran ring of 4-[(N-imidazol-2-ylmethyl)-4-chloroanilino]benzopyran, previously discovered as anti-angiogenic agent with antitumor activity, with pyranopyridines. The [3,2-c]-, [3,2-b]-, [2,3-c]-, and [2,3-b]-pyranopyridines with -(imidazol-2-ylmethyl)aniline moiety at the 4-position, were synthesized respectively, an...

KR-31831 ((2S,3R,4S)-4-(((1H-imidazol-2-yl)methyl)(4-chlorophenyl)amino)-6-amino-2-(dimethoxymethyl)-2-methyl-3,4-dihydro-2H-chromen-3-ol) is a novel antiangiogenic agent. In vitro and in vivo metabolism of KR-31831 in rats has been investigated using LC-MS and LC-MS/MS analysis. Incubation of rat liver microsomes and hepatocytes with KR-31831 prod...

A series of 4-substituted (benzo[b]thiophene-2-carbonyl)guanidines was synthesized and evaluated for the NHE-1 inhibitory activity and cardioprotective efficacy both in vitro and in vivo. Several analogs exhibited a strong inhibition on NHE-1, and which was generally well correlated with their cardioprotective efficacy. Especially the 4-nitro 20 an...

A series of (5-arylfuran-2-ylcarbonyl)guanidines was synthesized and evaluated for the NHE-1 inhibitory activity and cardiprotective efficacy against ischemia-reperfusion injury. Starting with (5-phenylfuran-2-ylcarbonyl)guanidine 47 with a moderate inhibitory effect on NHE-1, the compounds with various substituents at the phenyl ring were investig...

The present study was performed to evaluate the cardioprotective effects of [5-(2-methoxy-5-chloro-5-phenyl)furan-2-ylcarbonyl]guanidine (KR-32570) on ischemia/reperfusion-induced mechanical and metabolic dysfunction in isolated rat hearts. In addition, the effects of KR-32570 on the Na(+)/H(+)-exchanger (NHE) and lipid peroxidation were also evalu...

A novel compound KR-31378 [(2S,3S,4R)-N''-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methly-2-dimethoxy-methly-2H-benzo-pyran-4-yl)-N-benzylguanidine] has been demonstrated as an anti-ischemic agent in rat heart and brain. Here, we report the effects of this compound on hypoxia-induced cell death and possible signaling pathways in heart-derived H9c2...

This study reports the absorption, dose-linearity and pharmacokinetics of a novel antiangiogenic agent KR-31831 in rats after i.v. and oral administration at doses of 5, 10 and 25 mg/kg on both occasions. Concentrations of KR-31831 were determined by a validated LC/MS/MS assay method. After i.v. injection, plasma concentration-time profiles showed...

A novel class of alkoxybenzylcyanoguanidine analogs as the inhibitors of restenosis was discovered, which showed the inhibitory effects on angiotensin II-induced cell proliferation, determined by [3H]thymidine incorporation method. The compound, N′-(4-nitrophenyl)guanidine analog 19, showed 62% inhibition of [3H]thymidine incorporation at 1 μM conc...

In this study, we attempted to prepare compounds with heterocyclic replacements for metabolically unstable esters of benzopyranyl indole-2-carboxylic esters, which showed good in vitro and in vivo cardioprotective efficacies possibly through the opening of mitochondrial ATP-sensitive potassium channel (). Initially, we tried to construct indolin-2-...

In the present study, we investigated whether a novel benzopyranylindol analogue, KR-31466 (KR466) (1-[(2S,3R,4S)-3,4-dihydro-2-dimethoxymethyl-3-hydroxy-2-methyl-6-nitro-2H-1-benzopyran-4-yl]-1H-indole-2-carboxylic acid ethyl ester) can attenuate hypoxic injury in heart-derived H9c2 cells and, if so, whether the protective effect of KR466 is media...

This paper describes the design, syntheses, and biological evaluations of novel ATP-sensitive potassium channel (K(ATP)) openers, benzopyranyl indoline and indole derivatives. Among those, two enantiomers of indoline-2-carboxylic ethyl esters (14, 18) showed the best cardioprotective activities both in vitro and in vivo, while their vasorelaxation...

A series of 4-(N-imidazol-2-ylmethyl)aminobenzopyran analogues, originally designed as K(ATP) openers for ischemic diseases, showed antiangiogenic properties through the inhibition of HUVEC tube formation. Especially one of p-Cl substituted analogues (4c) completely inhibited HUVEC tube formation at 10 microM. The compound 4c significantly inhibite...

This paper describes the design, synthesis, and biological evaluation of a novel anti-ischemic compound, (2S,3S,4R)-N-(6-amino-3,4-dihydro-2-dimethoxymethyl-3-hydroxy-2-methyl-2H-benzopyranyl)-N'-benzyl-N"-cyanoguanidine (33), and the structure-activity relationships leading to the discovery of this compound. Compound 33 significantly reduced the m...

8-Methoxy-2-tetralone (6) can be easily prepared in approximately 50% overall yield starting from 2-bromophenylacetic acid (1), utilizing a Friedel-Crafts acylation/cyclization, ketone protection, copper(I)-catalyzed methoxylation of the aromatic bromide in the presence of an ester as a co-catalyst, and ketone deprotection.

Benzofuran-7-carboxamide was identified as a novel scaffold of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor. A series of compounds with various 2-substituents including (tertiary amino)methyl moieties sub-stituted with aryl ring and aryl groups containing tertiary amines, were synthesized and biologically evaluated to elucidate the structure-ac...

Three types of ergolines, having a substituent in ring A were designed and their total syntheses were attempted. N -substituted 12-methoxyergolines were synthesized as potential serotonergic agents to test the hypothesis of bioisosterism between the C8 carbonyl oxygen of LSD and an ortho oxygen or a 5-oxygen atom in hallucinogenic phenethylamines a...