4Y73

Crystal structure of IRAK4 kinase domain with inhibitor

Summary for 4Y73

• Entry DOI: 10.2210/pdb4y73/pdb
• Descriptor: Interleukin-1 receptor-associated kinase 4, 5-{[(1R,2S)-2-aminocyclohexyl]amino}-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (3 entities in total)
• Functional Keywords: kinase, inhibitor, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : Q9NWZ3
• Total number of polymer chains: 4
• Total formula weight: 137742.62

Authors

Lesburg, C.A. (deposition date: 2015-02-13, release date: 2015-05-20, Last modification date: 2024-10-16)

Primary citation

Lim, J.,Altman, M.D.,Baker, J.,Brubaker, J.D.,Chen, H.,Chen, Y.,Fischmann, T.,Gibeau, C.,Kleinschek, M.A.,Leccese, E.,Lesburg, C.,Maclean, J.K.,Moy, L.Y.,Mulrooney, E.F.,Presland, J.,Rakhilina, L.,Smith, G.F.,Steinhuebel, D.,Yang, R.
Discovery of 5-Amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide Inhibitors of IRAK4.
Acs Med.Chem.Lett., 6:683-688, 2015

PubMed Abstract: Interleukin-1 receptor associated kinase 4 (IRAK4) is an essential signal transducer downstream of the IL-1R and TLR superfamily, and selective inhibition of the kinase activity of the protein represents an attractive target for the treatment of inflammatory diseases. A series of 5-amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamides was developed via sequential modifications to the 5-position of the pyrazolopyrimidine ring and the 3-position of the pyrazole ring. Replacement of substituents responsible for poor permeability and improvement of physical properties guided by cLogD led to the identification of IRAK4 inhibitors with excellent potency, kinase selectivity, and pharmacokinetic properties suitable for oral dosing.

PubMed: 26101574
DOI: 10.1021/acsmedchemlett.5b00107

Experimental method

X-RAY DIFFRACTION (2.14 Å)