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

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ICR Authors

Meier, Pascal

Authors

Salla, M
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

Document Type

Journal Article

Date

2018-05-01

Date Accepted

2018-02-26

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.

Citation

The Journal of pharmacology and experimental therapeutics, 2018, 365 (2), pp. 354 - 367

DOI

10.1124/jpet.117.247163

URI

https://repository.icr.ac.uk/handle/internal/3133

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Source Title

Publisher

AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS

ISSN

0022-3565

eISSN

1521-0103

Collections

Breast Cancer Research

Research Team

Cell Death and Immunity

Notes