Cited by 158Protein Kinase Regulation and GTPase SignalingProtein Tyrosine PhosphatasesEnzyme Structure and Function

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The Structure of JNK3 in Complex with Small Molecule Inhibitors

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Scapin, Giovanna, Patel, Sangita B., Lisnock, JeanMarie, Becker, Joseph W., LoGrasso, Philip V.·2003·Chemistry & Biology

DOI 10.1016/s1074-5521(03)00159-5

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Abstract

The c-Jun terminal kinases (JNKs) are members of the mitogen-activated protein (MAP) kinase family and regulate signal transduction in response to environmental stress. Activation of JNK3, a neuronal-specific isoform, has been associated with neurological damage, and as such, JNK3 may represent an attractive target for the treatment of neurological disorders. The MAP kinases share between 50% and 80% sequence identity. In order to obtain efficacious and safe compounds, it is necessary to address the issues of potency and selectivity. We report here four crystal structures of JNK3 in complex with three different classes of inhibitors. These structures provide a clear picture of the interactions that each class of compound made with the kinase. Knowledge of the atomic interactions involved in these diverse binding modes provides a platform for structure-guided modification of these compounds, or the de novo design of novel inhibitors that could satisfy the need for potency and selectivity.

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[20] Processing of X-ray diffraction data collected in oscillation mode
Otwinowski, Z., & Minor, W. (1997) · Methods in Enzymology · doi:10.1016/s0076-6879(97)76066-x · Cited by 33,475
Crystallography & NMR System: A New Software Suite for Macromolecular Structure Determination
Brünger, A. T., Adams, P. D., Clore, G. M., DeLano, W. L., Gros, P., Grosse‐Kunstleve, R. W., Jiang, J., Kuszewski, J. J., Nilges, M., Pannu, N., et al. (1998) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444998003254 · Cited by 15,723
Improved methods for building protein models in electron density maps and the location of errors in these models
Jones, T. A., Zou, J.-Y., Cowan, S. W., & Kjeldgaard, M. (1991) · Acta Crystallographica Section A Foundations of Crystallography · doi:10.1107/s0108767390010224 · Cited by 12,616
Mammalian MAP kinase signalling cascades
Chang, L., & Karin, M. (2001) · Nature · doi:10.1038/35065000 · Cited by 5,118
AMoRe: an automated package for molecular replacement
Navaza, J. (1994) · Acta Crystallographica Section A Foundations of Crystallography · doi:10.1107/s0108767393007597 · Cited by 4,941
Crystallographic Computing 6
Flack, H. D., Párkányi, L., & Simon, K. (1993) · doi:10.1093/oso/9780198557883.001.0001 · Cited by 2,003
Structural Mechanism for STI-571 Inhibition of Abelson Tyrosine Kinase
Schindler, T. H., Bornmann, W. G., Pellicena, P., Miller, W. T., Clarkson, B., & Kuriyan, J. (2000) · Science · doi:10.1126/science.289.5486.1938 · Cited by 1,785
Selective interaction of JNK protein kinase isoforms with transcription factors.
Gupta, S., Barrett, T., Whitmarsh, A. J., Cavanagh, J., Sluss, H. K., Dérijard, B., & Davis, R. J. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb00636.x · Cited by 1,341
Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene
Yang, D. D., Kuan, C.-Y., Whitmarsh, A. J., Rinócn, M., Zheng, T. S., Davis, R. J., RAKIC, P. T., & Flavell, R. A. (1997) · Nature · doi:10.1038/39899 · Cited by 1,230
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Mohammadi, M., McMahon, G., Sun, L., Tang, C., Hirth, P., Yeh, B. K., Hubbard, S. R., & Schlessinger, J. (1997) · Science · doi:10.1126/science.276.5314.955 · Cited by 1,099

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Retracted
Three-dimensional quantitative structure–activity relationship (3 D-QSAR) and docking studies on (benzothiazole-2-yl) acetonitrile derivatives as c-Jun N-terminal kinase-3 (JNK3) inhibitors
Shaikh, A. R., Ismael, M., Carpio, C. A. D., Tsuboi, H., Koyama, M., Endou, A., Kubo, M., Brocławik, E., & Miyamoto, A. (2006) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2006.06.039 · Cited by 32
Synthesis and SAR of 1,9-dihydro-9-hydroxypyrazolo[3,4-b]quinolin-4-ones as novel, selective c-Jun N-terminal kinase inhibitors
Liu, M., Xin, Z., Clampit, J. E., Wang, S., Gum, R. J., Haasch, D. L., Trevillyan, J. M., Abad‐Zapatero, C., Fry, E. H., Sham, H. L., et al. (2006) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2006.02.046 · Cited by 31
Structural Optimization of a Pyridinylimidazole Scaffold: Shifting the Selectivity from p38α Mitogen-Activated Protein Kinase to c-Jun N-Terminal Kinase 3
Ansideri, F., Macedo, J. T., Eitel, M., El‐Gokha, A., Zinad, D. S., Scarpellini, C., Kudolo, M., Schollmeyer, D., Boeckler, F. M., Blaum, B. S., et al. (2018) · ACS Omega · doi:10.1021/acsomega.8b00668 · Cited by 31
Arrestin-Dependent Activation of JNK Family Kinases
Zhan, X., Kook, S., Gurevich, E. V., & Gurevich, V. V. (2013) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-41199-1_13 · Cited by 27
“…purposes, but most of the inhibitors found so far are not sufficiently specific, as they inhibit other kinases besides JNKs (Bennett et al. 2001; Scapin et al. 2003; Carboni et al. 2004; Resnick and Fennell 2004; Wang et al. 2004; Sabapathy 2012) A cell-permeable peptide inhibitor containing a…”
BackgroundInfluential
Dissection of the Recognition Properties of p38 MAP Kinase. Determination of the Binding Mode of a New Pyridinyl−Heterocycle Inhibitor Family
Soliva, R., Gelpí, J. L., Almansa, C., Virgili, M., & Orozco, M. (2006) · Journal of Medicinal Chemistry · doi:10.1021/jm061073h · Cited by 25
Enzyme Kinetics and Interaction Studies for Human JNK1β1 and Substrates Activating Transcription Factor 2 (ATF2) and c-Jun N-terminal kinase (c-Jun)
Figuera-Losada, M., & LoGrasso, P. V. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.323766 · Cited by 23
Self-citation
Discovery of new JNK3 inhibitory chemotypes via QSAR-Guided selection of docking-based pharmacophores and comparison with other structure-based pharmacophore modeling methods
Tuffaha, G. O., Hatmal, M. M., & Taha, M. O. (2019) · Journal of Molecular Graphics and Modelling · doi:10.1016/j.jmgm.2019.05.015 · Cited by 24
Seven Cysteine-Deficient Mutants Depict the Interplay between Thermal and Chemical Stabilities of Individual Cysteine Residues in Mitogen-Activated Protein Kinase c-Jun N-Terminal Kinase 1
Nakaniwa, T., Fukada, H., Inoue, T., Gouda, M., Nakai, R., Kirii, Y., Adachi, M., Tamada, T., Segawa, S.-I., Kuroki, R., et al. (2012) · Biochemistry · doi:10.1021/bi300918w · Cited by 23
Fluorescence polarization-based assays for detecting compounds binding to inactive c-Jun N-terminal kinase 3 and p38α mitogen-activated protein kinase
Ansideri, F., Lange, A., El‐Gokha, A., Boeckler, F. M., & Koch, P. (2016) · Analytical Biochemistry · doi:10.1016/j.ab.2016.02.018 · Cited by 22
Exploration of a Binding Mode of Benzothiazol-2-yl Acetonitrile Pyrimidine Core Based Derivatives as Potent c-Jun N-Terminal Kinase-3 Inhibitors and 3D-QSAR Analyses
Sharma, P., & Ghoshal, N. (2006) · Journal of Chemical Information and Modeling · doi:10.1021/ci060057q · Cited by 22
A direct ELISA assay for quantitative determination of the inhibitory potency of small molecules inhibitors for JNK3
Goettert, M. I., Luik, S., Graeser, R., & Laufer, S. (2011) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2011.01.014 · Cited by 21
Aminopyridine carboxamides as c-Jun N-terminal kinase inhibitors: Targeting the gatekeeper residue and beyond
Liu, G., Zhao, H., Liu, B., Xin, Z., Liu, M., Kosogof, C., Szczepankiewicz, B. G., Wang, S., Clampit, J. E., Gum, R. J., et al. (2006) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2006.08.097 · Cited by 21
Discovery of Bis-imidazolecarboxamide Derivatives as Novel, Potent, and Selective TNIK Inhibitors for the Treatment of Idiopathic Pulmonary Fibrosis
Aladinskiy, V., Kruse, C. G., Qin, L., Babin, E., Fan, Y., Andreev, G., Zhao, H., Fu, Y., Zhang, M., Ivanenkov, Y. A., et al. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c01580 · Cited by 19
Identifying, cloning and structural analysis of differentially expressed genes upon Puccinia infection of Festuca rubra var. rubra
Ergen, N. Z., Doğanay, G. D., Shearman, R. C., & Budak, H. (2007) · Gene · doi:10.1016/j.gene.2007.02.005 · Cited by 19
The use of biophysical methods increases success in obtaining liganded crystal structures
Chung, C. (2006) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444906051869 · Cited by 19
“In some instances, nascent ligand pockets reveal themselves in the protein only when prompted to open up when an appropriate ligand is bound (Scapin et al., 2003).”
Background
Enhancing Industrial Hemp (Cannabis sativa) Leaf By-Products: Bioactive Compounds, Anti-Inflammatory Properties, and Potential Health Applications
Frusciante, L., Geminiani, M., Shabab, B., Olmastroni, T., Roncucci, N., Mastroeni, P., Salvini, L., Lamponi, S., Trezza, A., & Santucci, A. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26020548 · Cited by 20
“Target/Compound Interaction A docking simulation of compounds against MAPK10 and NF-κ B p65 was performed, allowing the compounds to bind in a known binding region of human MAPK10 inhibitors [50].”
Assessing potency of c-Jun N-terminal kinase 3 (JNK3) inhibitors using 2D molecular descriptors and binary QSAR methodology
Ijjaali, I., Petitet, F., Dubus, E., Barberan, O., & Michel, A. G. (2007) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2007.03.062 · Cited by 18
Disruption of the EGFR E884–R958 ion pair conserved in the human kinome differentially alters signaling and inhibitor sensitivity
Tang, Z., Jiang, S., Du, R., Petri, E. T., El-Telbany, A., Chan, P. S. O., Kijima, T., Dietrich, S., Matsui, K., Kobayashi, M., et al. (2008) · Oncogene · doi:10.1038/onc.2008.411 · Cited by 18
“, 2004), human JNK3 (PDB accession code: 1PMQ) (Scapin et al., 2003), human insulin receptor kinase (PDB accession code: 1IR3) (Hubbard, 1997), ZAP-70 tyrosine kinase (PDB accession code: 1U59) (Jin et al.”
On the in silico and in vitro anticancer activity of sulfonamide chalcones: potential JNKK3 inhibitors
Custódio, J. M. F., Moura, A. F., de Moraes, M. O., Pérez, C. N., & Napolitano, H. B. (2020) · New Journal of Chemistry · doi:10.1039/c9nj05612b · Cited by 17
Crystallization of MAP kinases
Lee, S., Zhou, T., & Goldsmith, E. J. (2006) · Methods · doi:10.1016/j.ymeth.2006.05.003 · Cited by 17
Cross-Reactivity Virtual Profiling of the Human Kinome by X-ReactKIN: A Chemical Systems Biology Approach
Bryliński, M., & Skolnick, J. (2010) · Molecular Pharmaceutics · doi:10.1021/mp1002976 · Cited by 16
Novel Tryptanthrin Derivatives with Selectivity as c–Jun N–Terminal Kinase (JNK) 3 Inhibitors
Schepetkin, I. A., Karpenko, O. S., Kovrizhina, A. R., Kirpotina, L. N., Khlebnikov, А. I., Chekal, S. I., Radudik, A. V., Shybinska, M. O., & Quinn, M. T. (2023) · Molecules · doi:10.3390/molecules28124806 · Cited by 15
“In this binding mode, the quinazolone moiety coincides with the experimentally determined position of SP600125 in PDB structure 1PMV [64].”
Background
Discovery of a novel small molecule PT109 with multi-targeted effects against Alzheimer's disease in vitro and in vivo
Chen, Q., Tu, Y., Mak, S., Chen, J., Lu, J., Chen, C., Yang, X., Wang, S., Wen, S., Ma, S., et al. (2020) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2020.173361 · Cited by 15
Considerations of Protein Subpockets in Fragment‐Based Drug Design
Bartolowits, M. D., & Davisson, V. J. (2015) · Chemical Biology & Drug Design · doi:10.1111/cbdd.12631 · Cited by 14
“An example can be seen with the JNK3 human kinase, where the residues Glu147, Met149, and Val196 form a microenvironment (Figure 2C) that recognizes shared chemical features between a natural ligand, adenosine monophosphate (AMP) (111), and a dihydroanthrapyrazole-based inhibitor (112), though their structures, overal…”
Background
Ligand-based and structure-based approaches in identifying ideal pharmacophore against c-Jun N-terminal kinase-3
Suneel Kumar, B. V. S., Kotla, R., Buddiga, R., Roy, J., Singh, S. S., Gundla, R., Ravikumar, M., & Sarma, J. A. R. P. (2010) · Journal of Molecular Modeling · doi:10.1007/s00894-010-0701-0 · Cited by 14
“In hinge region amino acids, Gln155 is the core of the selectivity for JNK3 and this amino acid is not conserved in other map kinases [18, 19].”
Background
Hemodynamic effects of potent and selective JNK inhibitors in anesthetized rats: Implication for targeting protein kinases in metabolic diseases
Liu, G., Zhao, H., Liu, B., Xin, Z., Liu, M., Serby, M. D., Lubbers, N. L., Widomski, D. L., Polakowski, J. S., Beno, D. W. A., et al. (2006) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2006.10.013 · Cited by 14
c-Jun N-terminal kinases 3 (JNK3) from orange-spotted grouper, Epinephelus coioides, inhibiting the replication of Singapore grouper iridovirus (SGIV) and SGIV-induced apoptosis
Guo, M., Wei, J., Zhou, Y., & Qin, Q. (2016) · Developmental & Comparative Immunology · doi:10.1016/j.dci.2016.06.009 · Cited by 13
Identifying New Ligands for JNK3 by Fluorescence Thermal Shift Assays and Native Mass Spectrometry
Cheng, C., Liu, M., Gao, X., Wu, D., Pu, M., Ma, J., Quinn, R. J., Xiao, Z., & Liu, Z. (2022) · ACS Omega · doi:10.1021/acsomega.2c00340 · Cited by 12
Bioactive Potential of Sweet Cherry (Prunus avium L.) Waste: Antioxidant and Anti-Inflammatory Properties for Sustainable Applications
Frusciante, L., Nyong'a, C. N., Trezza, A., Shabab, B., Olmastroni, T., Barletta, R., Mastroeni, P., Visibelli, A., Orlandini, M., Raucci, L., et al. (2025) · Foods · doi:10.3390/foods14091523 · Cited by 11
LASSBio‐1829 Hydrochloride: Development of a New Orally Active N‐Acylhydrazone IKK2 Inhibitor with Anti‐inflammatory Properties
Guedes, I. A., de Freitas, R. H. C. N., Cordeiro, N. D. M., do Nascimento, T. S., Valerio, T. S., Fernandes, P. D., Dardenne, L. E., & Fraga, C. A. M. (2015) · ChemMedChem · doi:10.1002/cmdc.201500266 · Cited by 11
Substituting c-Jun N-terminal kinase-3 (JNK3) ATP-binding site amino acid residues with their p38 counterparts affects binding of JNK- and p38-selective inhibitors
Fricker, M., LoGrasso, P. V., Ellis, S., Wilkie, N. M., Hunt, P. A., & Pollack, S. J. (2005) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2005.04.013 · Cited by 11
Self-citation
JNK Mediates Differentiation, Cell Polarity and Apoptosis During Amphioxus Development by Regulating Actin Cytoskeleton Dynamics and ERK Signalling
Somorjai, I., Ehebauer, M. T., Escrivá, H., & García‐Fernàndez, J. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.749806 · Cited by 10
“A comparative model of the B. belcheri JNK MAP kinase, residues N47 to S403, was created using Modeller 10.1 (Webb and Sali, 2016) based on the coordinates of residue D45 to N400 of human MAPK10 (1PMV) (Scapin et al., 2003).”
MethodInfluential
Targeting JNK3 for Alzheimer's disease: Design and synthesis of novel inhibitors with aryl group diversity utilizing wide pocket
Kim, H., Park, H., Jun, J., Moon, J., Oh, J., Bhujbal, S. P., & Hah, J. (2025) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2024.117209 · Cited by 10
Anthrapyrazolone analogues intercept inflammatory JNK signals to moderate endotoxin induced septic shock
Karothu, D. P., Trinath, J., Biswas, A., Sekar, K., Balaji, K. N., & Row, T. N. G. (2014) · Scientific Reports · doi:10.1038/srep07214 · Cited by 10
Achieving High Quality Ligand Chemistry in Protein-Ligand Crystal Structures for Drug Design
Smart, O. S., & Bricogne, G. (2015) · NATO science for peace and security series. A, Chemistry and biology · doi:10.1007/978-94-017-9719-1_13 · Cited by 10
“1PMQ is the structure of JNK3 in complex with an imidazole-pyrimidine inhibitor, solved in 2003 by Giovanna Scapin and colleagues at Merck (Scapin et al., 2003).”
Background
Lead Generation and Optimization Based on Protein-Ligand Complementarity
Ogata, K., Isomura, T., Kawata, S., Yamashita, H., Kubodera, H., & Wodak, S. J. (2010) · Molecules · doi:10.3390/molecules15064382 · Cited by 10
Dihydroartemisinin as a potential drug candidate for cancer therapy: a structural-based virtual screening for multitarget profiling
Malami, I., Bunza, A. M., Alhassan, A. M., Muhammad, A. I., Abubakar, I. B., Yunusa, A., Waziri, P. M., & Etti, I. C. (2020) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2020.1824811 · Cited by 9
“The binding pattern of DHA in the residues lining the ATP binding sites of MARKs are near similar to that reported by other (Anderson et al., 2007; Gill et al., 2005; Heo et al., 2004; Scapin et al., 2003).”
Result

Authors: Scapin, G., Patel, S. B., Lisnock, J., Becker, J. W., & LoGrasso, P. V.
Affiliations: Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
Corresponding author: Scapin, Giovanna
ORCID: Scapin, Giovanna
Venue: Chemistry & Biology
Publisher: Elsevier BV
Published: 2003-08
Volume: 10
Issue: 8
Pages: 705-712
ISSN: 1074-5521 (ISSN-L)
DOI: 10.1016/s1074-5521(03)00159-5
OpenAlex: W1891159913
Cited by: 131
References: 47
Citations by year: 2026: 4 · 2025: 7 · 2024: 5 · 2023: 4 · 2022: 2 · 2021: 2 · 2020: 7 · 2019: 2 · 2018: 3 · 2016: 7 · 2015: 4 · 2014: 4 · 2013: 4 · 2012: 6
FWCI: 3.56
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 3638 d)
Locations: Chemistry & Biology (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
Keywords: JNK3, c-Jun N-terminal kinase, mitogen-activated protein kinase, kinase inhibitors, small molecule inhibitors, binding mode, kinase selectivity, structure-based drug design, neurological disorders, neuroprotection
MeSH terms: Adenosine Triphosphate, Binding Sites, Enzyme Inhibitors, Models, Molecular, Protein Conformation, Protein-Tyrosine Kinases, Recombinant Proteins, Structure-Activity Relationship, Crystallography, X-Ray, Mitogen-Activated Protein Kinases, p38 Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase 10

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The Structure of JNK3 in Complex with Small Molecule Inhibitors

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