6ANL

Structure-based Design, Synthesis, and Biological Evaluation of Imidazo[1,2-b]pyridazine-based p38 MAP Kinase Inhibitors

Summary for 6ANL

• Entry DOI: 10.2210/pdb6anl/pdb
• Related: 5WJJ
• Descriptor: Mitogen-activated protein kinase 14, TAK-715 (3 entities in total)
• Functional Keywords: transferase-transferase inhibitor complex, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : Q16539
• Total number of polymer chains: 1
• Total formula weight: 42114.03

Authors

Snell, G.P.,Okada, K.,Bragstad, K.,Sang, B.-C. (deposition date: 2017-08-14, release date: 2018-01-17, Last modification date: 2024-03-13)

Primary citation

Kaieda, A.,Takahashi, M.,Takai, T.,Goto, M.,Miyazaki, T.,Hori, Y.,Unno, S.,Kawamoto, T.,Tanaka, T.,Itono, S.,Takagi, T.,Hamada, T.,Shirasaki, M.,Okada, K.,Snell, G.,Bragstad, K.,Sang, B.C.,Uchikawa, O.,Miwatashi, S.
Structure-based design, synthesis, and biological evaluation of imidazo[1,2-b]pyridazine-based p38 MAP kinase inhibitors.
Bioorg. Med. Chem., 26:647-660, 2018

PubMed Abstract: We identified novel potent inhibitors of p38 MAP kinase using structure-based design strategy. X-ray crystallography showed that when p38 MAP kinase is complexed with TAK-715 (1) in a co-crystal structure, Phe169 adopts two conformations, where one interacts with 1 and the other shows no interaction with 1. Our structure-based design strategy shows that these two conformations converge into one via enhanced protein-ligand hydrophobic interactions. According to the strategy, we focused on scaffold transformation to identify imidazo[1,2-b]pyridazine derivatives as potent inhibitors of p38 MAP kinase. Among the herein described and evaluated compounds, N-oxide 16 exhibited potent inhibition of p38 MAP kinase and LPS-induced TNF-α production in human monocytic THP-1 cells, and significant in vivo efficacy in rat collagen-induced arthritis models. In this article, we report the discovery of potent, selective and orally bioavailable imidazo[1,2-b]pyridazine-based p38 MAP kinase inhibitors with pyridine N-oxide group.

PubMed: 29291937
DOI: 10.1016/j.bmc.2017.12.031

Experimental method

X-RAY DIFFRACTION (2 Å)