4YO6
Irak4-inhibitor co-structure
4YO6 の概要
エントリーDOI | 10.2210/pdb4yo6/pdb |
分子名称 | Interleukin-1 receptor-associated kinase 4, N-(3-methyl-1-phenyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (3 entities in total) |
機能のキーワード | kinase, phosphatase, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
由来する生物種 | Homo sapiens (Human) |
細胞内の位置 | Cytoplasm : Q9NWZ3 |
タンパク質・核酸の鎖数 | 4 |
化学式量合計 | 137416.45 |
構造登録者 | |
主引用文献 | McElroy, W.T.,Tan, Z.,Ho, G.,Paliwal, S.,Li, G.,Seganish, W.M.,Tulshian, D.,Tata, J.,Fischmann, T.O.,Sondey, C.,Bian, H.,Bober, L.,Jackson, J.,Garlisi, C.G.,Devito, K.,Fossetta, J.,Lundell, D.,Niu, X. Potent and Selective Amidopyrazole Inhibitors of IRAK4 That Are Efficacious in a Rodent Model of Inflammation. Acs Med.Chem.Lett., 6:677-682, 2015 Cited by PubMed Abstract: IRAK4 is a critical upstream kinase in the IL-1R/TLR signaling pathway. Inhibition of IRAK4 is hypothesized to be beneficial in the treatment of autoimmune related disorders. A screening campaign identified a pyrazole class of IRAK4 inhibitors that were determined by X-ray crystallography to exhibit an unusual binding mode. SAR efforts focused on the identification of a potent and selective inhibitor with good aqueous solubility and rodent pharmacokinetics. Pyrazole C-3 piperidines were well tolerated, with N-sulfonyl analogues generally having good rodent oral exposure but poor solubility. N-Alkyl piperidines exhibited excellent solubility and reduced exposure. Pyrazoles possessing N-1 pyridine and fluorophenyl substituents were among the most active. Piperazine 32 was a potent enzyme inhibitor with good cellular activity. Compound 32 reduced the in vivo production of proinflammatory cytokines and was orally efficacious in a mouse antibody induced arthritis disease model of inflammation. PubMed: 26101573DOI: 10.1021/acsmedchemlett.5b00106 主引用文献が同じPDBエントリー |
実験手法 | X-RAY DIFFRACTION (2.32 Å) |
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