Thiazolidine-2,4-dione-based irreversible allosteric IKK-β kinase inhibitors: Optimization into in vivo active anti-inflammatory agents.

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ID: 78122
2019
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Abstract
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-β. Herein, we address optimization into in vivo active anti-inflammatory agents. We successfully developed potent IKK-β inhibitors with the most potent compound eliciting IC = 0.20 μM. 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-β with verified in vitro and in vivo anti-inflammatory activity.
Reference Key
elkamhawy2019thiazolidine24dionebasedeuropean Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors 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;
Journal European journal of medicinal chemistry
Year 2019
DOI
S0223-5234(19)31107-9
URL
Keywords
allosteric modulation anti-inflammatory ikk-β modulators nf-κb signaling pathway thiazolidine-2,4-diones

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