Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• European journal of medicinal chemistry, 2020-02, Vol.188, p.111955-111955, Article 111955

Ort / Verlag

France: Elsevier Masson SAS

Erscheinungsjahr

2020

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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 IC50 = 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. [Display omitted] 7aIrreversible allosteric IKK-β inhibitor IC50 = 200 nMKinact = 0.013 min−1TNF-α IC50 = 6.27 μMPGE2 IC50 = 9.83 μMPlasma stability = 73.6% after two hoursMicrosomal stability t1/2 = 1 hourIn vivo protection against septic shock = 80% survival at 36 h post injection. •Potent irreversible allosteric IKK-β inhibitors were developed.•Cellular assays elucidated significant in vitro anti-inflammatory activity.•In vitro evaluation of microsomal and plasma stabilities showed safe profile for analog 7a.•In vivo evaluation of 7a showed its ability to protect mice against septic shock induced mortality.