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 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.
journal_name
Eur J Med Chemjournal_title
European journal of medicinal chemistryauthors
Elkamhawy A,Kim NY,Hassan AHE,Park JE,Paik S,Yang JE,Oh KS,Lee BH,Lee MY,Shin KJ,Pae AN,Lee KT,Roh EJdoi
10.1016/j.ejmech.2019.111955subject
Has Abstractpub_date
2020-02-15 00:00:00pages
111955eissn
0223-5234issn
1768-3254pii
S0223-5234(19)31107-9journal_volume
188pub_type
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