4YO6

Irak4-inhibitor co-structure

Summary for 4YO6

• Entry DOI: 10.2210/pdb4yo6/pdb
• Descriptor: 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)
• Functional Keywords: kinase, phosphatase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : Q9NWZ3
• Total number of polymer chains: 4
• Total formula weight: 137416.45

Authors

Fischmann, T.O. (deposition date: 2015-03-11, release date: 2015-05-20, Last modification date: 2024-11-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.32 Å)