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Cellular and In Vivo Properties of MPI‐0485520, a Novel and Potent Small Molecule Inhibitor of IKKe
Author(s) -
Richards Burt,
Cronin Monica,
Seager Nathan,
Niederjohn Jenny,
Baichwal Vijay,
Chan Ashley,
Robinson Rosann,
Hess Mark,
Davis Thaylon,
Papac Damon,
Suzuki Kazuyuki,
Holcomb Ryan,
Carlson Robert
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.753.6
Subject(s) - in vivo , pharmacology , inflammation , bioavailability , chemistry , diabetes mellitus , medicine , endocrinology , biology , microbiology and biotechnology
Inhibitor kappaB kinase epsilon (IKKe) is involved in regulating the innate immune response against pathogens. Recently a role for IKKe in chronic inflammation associated with obesity and diabetes has been described. We have developed a small molecule IKKe inhibitor, MPI‐0485520, that has a Ki of 500 pM and shows good selectivity. MPI‐0485520 potently inhibits secretion of RANTES and phosphorylation of the IKKe substrate IRF3 in cellular models. In mice, MPI‐0485520 has high oral bioavailability and shows no adverse effects with daily dosing over a period of three weeks. To monitor inhibition of IKKe in vivo , effects on poly(I:C) induction of interferon‐stimulated gene 54 (ISG54) and ISG56 mRNA were measured in mice. Intraperitoneal injection of 200 micrograms of poly(I:C) dramatically induced ISG54 and ISG56 in liver and a single dose of 30 or 100 mg/kg MPI‐0485520 resulted in >60% and 100% inhibition of both, respectively. In contrast, no effect on induced IL‐6 or TNF‐alpha in liver was observed, demonstrating IKKe inhibitor selectivity. Potent, selective, and orally bioavailable IKKe inhibitors may have application for treating diseases associated with chronic inflammation such as obesity and diabetes.