Journal
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Volume 365, Issue 2, Pages 354-367Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/jpet.117.247163
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Funding
- Alberta Innovates - Health Solutions CRIO
- Alberta Heritage Foundation for Medical Research
- Department of Pediatrics/Stollery Children's Hospital-WCHRI Hair Massacure Donation Fund
- CONACyT (Mexico) [510728/288862]
- division of Hematology/Oncology/Palliative Care/Epidemiology
- Alberta Innovates [201600099] Funding Source: researchfish
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Receptor-interacting protein kinase 2 (RIP2 or RICK, herein referred to as RIPK2) is linked to the pathogen pathway that activates nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) 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 NFkB 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.
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