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

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

  • Eur J Med Chem. 2020 Feb 15;188:111955. doi: 10.1016/j.ejmech.2019.111955.
Ahmed Elkamhawy 1,  Nam Youn Kim 2,  Ahmed H E Hassan 3,  Jung-Eun Park 2,  Sora Paik 4,  Jeong-Eun Yang 2,  Kwang-Seok Oh 5,  Byung Ho Lee 5,  Mi Young Lee 5,  Kye Jung Shin 6,  Ae Nim Pae 7,  Kyung-Tae Lee 8,  Eun Joo Roh 9
Affiliations

Affiliations

  • 1 Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
  • 2 Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea.
  • 3 Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
  • 4 Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea; Department of Fundamental Pharmaceutical Sciences, College of Pharmacy, Kyung Hee University, Seoul, 02447, Republic of Korea.
  • 5 Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong, Daejeon, 34114, Republic of Korea.
  • 6 Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon-si, Gyeonggi-do, 14662, Republic of Korea.
  • 7 Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul, 02792, Republic of Korea.
  • 8 Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul, 02447, Republic of Korea.
  • 9 Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul, 02792, Republic of Korea. Electronic address: r8636@kist.re.kr.
PMID: 31893550 DOI: 10.1016/j.ejmech.2019.111955
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.

Keywords

Allosteric modulation; Anti-inflammatory; IKK-β modulators; NF-κB signaling pathway; Thiazolidine-2,4-diones.

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