4YP8

Irak4-inhibitor co-structure

4YP8 の概要

• エントリーDOI: 10.2210/pdb4yp8/pdb
• 分子名称: Interleukin-1 receptor-associated kinase 4, N-{1-(4-cyclopropyl-2-fluorophenyl)-3-[1-(propan-2-yl)piperidin-4-yl]-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: 137775.07

構造登録者

Fischmann, T.O. (登録日: 2015-03-12, 公開日: 2015-05-20, 最終更新日: 2024-10-09)

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

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: 26101573
DOI: 10.1021/acsmedchemlett.5b00106

実験手法

X-RAY DIFFRACTION (2.641 Å)