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Identification and Characterization of Novel Receptor-Interacting Serine/Threonine-Protein Kinase 2 Inhibitors Using Structural Similarity Analysis.

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Date
2018-05
ICR Author
Meier, Pascal
Author
Salla, M
Aguayo-Ortiz, R
Aguayo-Ortiz, R
Danmaliki, GI
Zare, A
Said, A
Moore, J
Pandya, V
Manaloor, R
Fong, S
Blankstein, AR
Gibson, SB
Garcia, LR
Meier, P
Bhullar, KS
Hubbard, BP
Fiteh, Y
Vliagoftis, H
Goping, IS
Brocks, D
Hwang, P
Velázquez-Martínez, CA
Baksh, S
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Type
Journal Article
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Abstract
Receptor-interacting protein kinase 2 (RIP2 or RICK, herein referred to as RIPK2) is linked to the pathogen pathway that activates nuclear factor κ-light-chain-enhancer of activated B cells (NFκB) and autophagic activation. Using molecular modeling (docking) and chemoinformatics analyses, we used the RIPK2/ponatinib crystal structure and searched in chemical databases for small molecules exerting binding interactions similar to those exerted by ponatinib. The identified RIPK2 inhibitors potently inhibited the proliferation of cancer cells by > 70% and also inhibited NFκB activity. More importantly, in vivo inhibition of intestinal and lung inflammation rodent models suggests effectiveness to resolve inflammation with low toxicity to the animals. Thus, our identified RIPK2 inhibitor may offer possible therapeutic control of inflammation in diseases such as inflammatory bowel disease, asthma, cystic fibrosis, primary sclerosing cholangitis, and pancreatitis.
URI
https://repository.icr.ac.uk/handle/internal/3133
DOI
https://doi.org/10.1124/jpet.117.247163
Collections
  • Breast Cancer Research
Subject
Cell Line, Tumor
Mitochondria
Humans
Colitis, Ulcerative
NF-kappa B
Protein Kinase Inhibitors
Apoptosis
Cell Proliferation
Catalytic Domain
Receptor-Interacting Protein Serine-Threonine Kinase 2
Drug Discovery
Cell Cycle Checkpoints
Molecular Docking Simulation
Research team
Cell Death and Immunity
Language
eng
Date accepted
2018-02-26
License start date
2018-05
Citation
The Journal of pharmacology and experimental therapeutics, 2018, 365 (2), pp. 354 - 367

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