Kim KR

References (9)

Title : Structural and Biophysical Analyses of Human N-Myc Downstream-Regulated Gene 3 (NDRG3) Protein - Kim_2020_Biomolecules_10_
Author(s) : Kim KR , Kim KA , Park JS , Jang JY , Choi Y , Lee HH , Lee DC , Park KC , Yeom YI , Kim HJ , Han BW
Ref : Biomolecules , 10 : , 2020
Abstract : The N-Myc downstream-regulated gene (NDRG) family belongs to the alpha/beta-hydrolase fold and is known to exert various physiologic functions in cell proliferation, dierentiation, and hypoxia-induced cancer metabolism. In particular, NDRG3 is closely related to proliferation and migration of prostate cancer cells, and recent studies reported its implication in lactate-triggered hypoxia responses or tumorigenesis. However, the underlying mechanism for the functions of NDRG3 remains unclear. Here, we report the crystal structure of human NDRG3 at 2.2 resolution, with six molecules in an asymmetric unit. While NDRG3 adopts the alpha/beta-hydrolase fold, complete substitution of the canonical catalytic triad residues to non-reactive residues and steric hindrance around the pseudo-active site seem to disable the alpha/beta-hydrolase activity. While NDRG3 shares a high similarity to NDRG2 in terms of amino acid sequence and structure, NDRG3 exhibited remarkable structural differences in a flexible loop corresponding to helix alpha6 of NDRG2 that is responsible for tumor suppression. Thus, this flexible loop region seems to play a distinct role in oncogenic progression induced by NDRG3. Collectively, our studies could provide structural and biophysical insights into the molecular characteristics of NDRG3.
ESTHER : Kim_2020_Biomolecules_10_
PubMedSearch : Kim_2020_Biomolecules_10_
PubMedID: 31935861
Gene_locus related to this paper: human-NDRG3

Title : Discovery of beta-aminoacyl containing thiazolidine derivatives as potent and selective dipeptidyl peptidase IV inhibitors - Park_2011_Bioorg.Med.Chem.Lett_21_1366
Author(s) : Park WS , Kang SK , Jun MA , Shin MS , Kim KY , Rhee SD , Bae MA , Kim MS , Kim KR , Kang NS , Yoo SE , Lee JO , Song DH , Silinski P , Schneider SE , Ahn JH , Kim SS
Ref : Bioorganic & Medicinal Chemistry Lett , 21 :1366 , 2011
Abstract : A series of beta-aminoacyl containing thiazolidine derivatives was synthesized and evaluated for their ability to inhibit DPP-IV. Several thiazolidine derivatives with an acid moiety were found to be potent DPP-IV inhibitors. Among them, compound 2da is the most active in this series with an IC(50) value of 1 nM, and it showed excellent selectivity over DPP-IV related enzymes including DPP-2, DPP-8, and DPP-9. Compound 2da is chemically and metabolically stable, and showed no CYP inhibition, hERG binding or cytotoxicity. Compound 2db, an ester prodrug of 2da, showed good in vivo DPP-IV inhibition after oral administration in rat and dog models.
ESTHER : Park_2011_Bioorg.Med.Chem.Lett_21_1366
PubMedSearch : Park_2011_Bioorg.Med.Chem.Lett_21_1366
PubMedID: 21306895
Gene_locus related to this paper: human-DPP4

Title : Synthesis and biological evaluation of pyrazoline analogues with beta-amino acyl group as dipeptidyl peptidase IV inhibitors - Jun_2008_Eur.J.Med.Chem_43_1889
Author(s) : Jun MA , Park WS , Kang SK , Kim KY , Kim KR , Rhee SD , Bae MA , Kang NS , Sohn SK , Kim SG , Lee JO , Lee DH , Cheon HG , Kim SS , Ahn JH
Ref : Eur Journal of Medicinal Chemistry , 43 :1889 , 2008
Abstract : A series of pyrazoline derivatives with beta-amino acyl group were synthesized and evaluated for their ability to inhibit dipeptidyl peptidase IV. Several pyrazoline derivatives exhibited submicromolar inhibitory activities against DPP-IV. X-ray co-crystal structure of initial hit compound 1h was determined. Among this series, carboxylic acid substituted pyrazoline derivative 2u was the most active and greatly decreased the inhibitory activity toward CYP3A4 enzyme.
ESTHER : Jun_2008_Eur.J.Med.Chem_43_1889
PubMedSearch : Jun_2008_Eur.J.Med.Chem_43_1889
PubMedID: 18243422
Gene_locus related to this paper: human-DPP4

Title : Synthesis and biological evaluation of homopiperazine derivatives with beta-aminoacyl group as dipeptidyl peptidase IV inhibitors - Ahn_2008_Bioorg.Med.Chem.Lett_18_6525
Author(s) : Ahn JH , Park WS , Jun MA , Shin MS , Kang SK , Kim KY , Rhee SD , Bae MA , Kim KR , Kim SG , Kim SY , Sohn SK , Kang NS , Lee JO , Lee DH , Cheon HG , Kim SS
Ref : Bioorganic & Medicinal Chemistry Lett , 18 :6525 , 2008
Abstract : Compounds with homopiperazine skeleton are designed to find a potent DPP-IV inhibitor without inhibiting CYP. Thus a series of beta-aminoacyl-containing homopiperazine derivatives was synthesized and evaluated. Compounds with acid moiety were found to be potent inhibitors of DPP-IV without inhibiting CYP 3A4. More specifically, compound 7m showed nanomolar activity with no inhibition towards five subtypes of CYPs, was considered as a prototype for further derivatization. Based on its X-ray co-crystal structure with human DPP-IV, we identified compounds 7s and 7t which showed good in vitro activity, no CYP inhibition, and good selectivity.
ESTHER : Ahn_2008_Bioorg.Med.Chem.Lett_18_6525
PubMedSearch : Ahn_2008_Bioorg.Med.Chem.Lett_18_6525
PubMedID: 18996694
Gene_locus related to this paper: human-DPP4

Title : Synthesis, biological evaluation and structural determination of beta-aminoacyl-containing cyclic hydrazine derivatives as dipeptidyl peptidase IV (DPP-IV) inhibitors - Ahn_2007_Bioorg.Med.Chem.Lett_17_2622
Author(s) : Ahn JH , Shin MS , Jun MA , Jung SH , Kang SK , Kim KR , Rhee SD , Kang NS , Kim SY , Sohn SK , Kim SG , Jin MS , Lee JO , Cheon HG , Kim SS
Ref : Bioorganic & Medicinal Chemistry Lett , 17 :2622 , 2007
Abstract : Inhibitors of dipeptidyl peptidase IV (DPP-IV) have been shown to be effective treatments for type 2 diabetes. A series of beta-aminoacyl-containing cyclic hydrazine derivatives were synthesized and evaluated as DPP-IV inhibitors. One member of this series, (R)-3-amino-1-(2-benzoyl-1,2-diazepan-1-yl)-4-(2,4,5-trifluorophenyl)butan-1-one (10f), showed potent in vitro activity, good selectivity and in vivo efficacy in mouse models. Also, the binding mode of compound 10f was determined by X-ray crystallography.
ESTHER : Ahn_2007_Bioorg.Med.Chem.Lett_17_2622
PubMedSearch : Ahn_2007_Bioorg.Med.Chem.Lett_17_2622
PubMedID: 17331715
Gene_locus related to this paper: human-DPP4

Title : KR-62436, 6-{2-[2-(5-cyano-4,5-dihydropyrazol-1-yl)-2-oxoethylamino]ethylamino}nicotinonitr ile, is a novel dipeptidyl peptidase-IV (DPP-IV) inhibitor with anti-hyperglycemic activity - Kim_2005_Eur.J.Pharmacol_518_63
Author(s) : Kim KR , Rhee SD , Kim HY , Jung WH , Yang SD , Kim SS , Ahn JH , Cheon HG
Ref : European Journal of Pharmacology , 518 :63 , 2005
Abstract : Dipeptidyl peptidase-IV (DPP-IV) is involved in the inactivation of glucagon-like peptide-1 (GLP-1), a potent insulinotropic peptide. Thus, DPP-IV inhibition can be an effective approach to treat type 2 diabetes mellitus by potentiating insulin secretion. This study describes the biological effects of a new DPP-IV inhibitor, KR-62436 (6-{2-[2-(5-cyano-4,5-dihydropyrazol-1-yl)-2-oxoethylamino]ethylamino}nicotinonit rile) in vitro and in vivo. KR-62436 inhibited rat plasma DPP-IV, porcine kidney DPP-IV as well as human DPP-IV (Caco-2) with IC50 values of 0.78, 0.49, 0.14 microM, respectively. In addition, the compound (10 microM) almost completely inhibited DPP-IV-mediated degradation of GLP-1 in vitro. KR-62436 inhibited the enzyme in a competitive manner, and exhibited selectivity against several proteases including proline-specific proteases. In vivo efficacy of the compound was examined by using normal C57BL/6J mice and ob/ob mice, a type 2 diabetes animal model. Administration of KR-62436 to C57BL/6J mice either orally or subcutaneously resulted in the suppression of plasma DPP-IV activity, increase in intact GLP-1 and insulin levels in plasma. Furthermore, the plasma glucose concentrations during oral glucose tolerance test (OGTT) were reduced upon oral administration of KR-62436. This study demonstrates that KR-62436 could be a good lead compound for further development as a new anti-diabetic agent.
ESTHER : Kim_2005_Eur.J.Pharmacol_518_63
PubMedSearch : Kim_2005_Eur.J.Pharmacol_518_63
PubMedID: 16106524

Title : Inhibition of dipeptidyl peptidase IV by novel inhibitors with pyrazolidine scaffold - Cheon_2005_Biochem.Pharmacol_70_22
Author(s) : Cheon HG , Kim SS , Kim KR , Rhee SD , Yang SD , Ahn JH , Park SD , Lee JM , Jung WH , Lee HS , Kim HY
Ref : Biochemical Pharmacology , 70 :22 , 2005
Abstract : Inhibition of dipeptidyl peptidase IV (DPP-IV) activity has been reported to improve nutrient-stimulated insulin secretion through the stabilization of glucagon-like peptide (GLP-1). In the present study, we identified novel DPP-IV inhibitors of pyrazolidine derivatives (Compounds 1 and 2) and characterized their biological effects in vitro and in vivo. Compound 1, an isoleucine pyrazolidide with a phenyl urea group, inhibited rat plasma DPP-IV, porcine kidney DPP-IV, as well as human Caco-2 DPP-IV with IC(50) values of 1.70, 2.26, and 2.02 microM, respectively. Because of the poor pharmacokinetic properties of Compound 1, further optimization was carried out, leading to the discovery of Compound 2, which had similar in vitro activities. Compound 2 acted as a selective and competitive inhibitor of DPP-IV. MALDI-TOF mass spectrometric analysis proved that the compound (20 microM) effectively blocked the degradation of active GLP-1 peptide by 61%. Although similar in in vitro potency, marked improvement of in vivo efficacy and pharmacokinetic properties was seen with Compound 2. Oral administration of Compound 2 resulted in potent and rapid inhibition of circulating DPP-IV in C57BL/6J mice, with ED(50) values of 26mg/kg (s.c.) and 42mg/kg (p.o.). In addition, this compound improved glucose tolerance in ob/ob mice, as determined by an oral glucose tolerance test (OGTT). These results indicate that Compound 2 is a potent and selective DPP-IV inhibitor with oral anti-hyperglycemic activity in vivo.
ESTHER : Cheon_2005_Biochem.Pharmacol_70_22
PubMedSearch : Cheon_2005_Biochem.Pharmacol_70_22
PubMedID: 15893294

Title : Purification, refolding, and characterization of recombinant Pseudomonas fluorescens lipase - Kim_2005_Protein.Expr.Purif_39_124
Author(s) : Kim KR , Kwon DY , Yoon SH , Kim WY , Kim KH
Ref : Protein Expr Purif , 39 :124 , 2005
Abstract : Thermostable Pseudomonas fluorescens SIK W1 lipase (PFL), which is responsible for the spoilage of milk, was overexpressed as inclusion bodies in Escherichia coli. Renaturation of solubilized PFL was achieved by using size-exclusion protein refolding chromatography. The renatured enzyme was purified homogeneously using a combination of gel filtration and ion-exchange FPLC. Its specific activity was found to be enhanced in the presence of Ca2+. Secondary structural changes induced by Ca2+ were monitored by circular dichroism, which demonstrated that the activity increase of PFL in the presence of Ca2+ is strongly correlated with significant increases in alpha-helix and beta-sheet content. In the presence of Ca2+, the PFL structure was found resistant to denaturation by guanidine hydrochloride and to enzyme activity loss due to cosolvents like DMSO and trifluoroethanol, suggesting that Ca2+ plays an important role in inducing conformational changes and consequently in maintaining enzyme structural stability.
ESTHER : Kim_2005_Protein.Expr.Purif_39_124
PubMedSearch : Kim_2005_Protein.Expr.Purif_39_124
PubMedID: 15596368

Title : Pyrazolidine derivatives with heteroaryl urea as dipeptidyl peptidase IV inhibitors - Ahn_2005_Chem.Pharm.Bull.(Tokyo)_53_1048
Author(s) : Ahn JH , Jung SH , Kim JA , Song SB , Kwon SJ , Kim KR , Rhee SD , Park SD , Lee JM , Kim SS , Cheon HG
Ref : Chem Pharm Bull (Tokyo) , 53 :1048 , 2005
Abstract : In the continuation of efforts to modify the structure of our novel DP-IV inhibitors, a series of pyrazolidine derivatives with heteroaryl urea was synthesized and evaluated for their ability to inhibit dipeptidyl peptidase IV (DP-IV).
ESTHER : Ahn_2005_Chem.Pharm.Bull.(Tokyo)_53_1048
PubMedSearch : Ahn_2005_Chem.Pharm.Bull.(Tokyo)_53_1048
PubMedID: 16079547