Elkamhawy, Ahmed Kim, Nam Youn Hassan, Ahmed H. E. Park, Jung-eun Paik, Sora Yang, Jeong-Eun Oh, Kwang-Seok Lee, Byung Ho Lee, Mi Young Shin, Kye Jung Pae, Ae Nim Lee, Kyung-Tae Roh, Eun Joo 2024-01-19T18:03:28Z 2024-01-19T18:03:28Z 2021-09-05 2020-02-15 0223-5234 https://pubs.kist.re.kr/handle/201004/118955 Selective kinase inhibitors development is a cumbersome task because of ATP binding sites similarities across kinases. On contrast, irreversible allosteric covalent inhibition offers opportunity to develop novel selective kinase inhibitors. Previously, we reported thiazolidine-2,4-dione lead compounds eliciting in vitro irreversible allosteric inhibition of IKK-beta. Herein, we address optimization into in vivo active antiinflammatory agents. We successfully developed potent IKK-beta inhibitors with the most potent compound eliciting IC50 = 0.20 mu M. Cellular assay of a set of active compounds using bacterial endotoxin lipopolysaccharide (LPS)-stimulated macrophages elucidated significant in vitro anti-inflammatory activity. In vitro evaluation of microsomal and plasma stabilities showed that the promising compound 7a is more stable than compound 7p. Finally, in vivo evaluation of 7a, which has been conducted in a model of LPS-induced septic shock in mice, showed its ability to protect mice against septic shock induced mortality. Accordingly, this study presents compound 7a as a novel potential irreversible allosteric covalent inhibitor of IKK-beta with verified in vitro and in vivo anti-inflammatory activity. (C) 2019 Elsevier Masson SAS. All rights reserved. English ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER NF-KAPPA-B BIOLOGICAL EVALUATION MACROPHAGE ACTIVATION ALPHA PRODUCTION DESIGN LIPOPOLYSACCHARIDE DISCOVERY PHOSPHORYLATION INFLAMMATION EXPRESSION Thiazolidine-2,4-dione-based irreversible allosteric IKK-beta kinase inhibitors: Optimization into in vivo active anti-inflammatory agents Article 10.1016/j.ejmech.2019.111955 1 EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v.188 EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 188 scie scopus 000515428100021 2-s2.0-85076947676 Chemistry, Medicinal Pharmacology & Pharmacy Article NF-KAPPA-B BIOLOGICAL EVALUATION MACROPHAGE ACTIVATION ALPHA PRODUCTION DESIGN LIPOPOLYSACCHARIDE DISCOVERY PHOSPHORYLATION INFLAMMATION EXPRESSION IKK-beta modulators NF-kappa B signaling pathway Thiazolidine-2,4-diones Allosteric modulation Anti-inflammatory