4XS2

Irak4-inhibitor co-structure

Summary for 4XS2

• Entry DOI: 10.2210/pdb4xs2/pdb
• Descriptor: Interleukin-1 receptor-associated kinase 4, (1R,2S,3R,5R)-3-({5-(1,3-benzothiazol-2-yl)-6-chloro-2-[(3-methoxypropyl)amino]pyrimidin-4-yl}amino)-5-(hydroxymethyl)cyclopentane-1,2-diol (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: 137744.70

Authors

Fischmann, T.O. (deposition date: 2015-01-21, release date: 2015-05-13, Last modification date: 2024-11-20)

Primary citation

McElroy, W.T.,Michael Seganish, W.,Jason Herr, R.,Harding, J.,Yang, J.,Yet, L.,Komanduri, V.,Prakash, K.C.,Lavey, B.,Tulshian, D.,Greenlee, W.J.,Sondey, C.,Fischmann, T.O.,Niu, X.
Discovery and hit-to-lead optimization of 2,6-diaminopyrimidine inhibitors of interleukin-1 receptor-associated kinase 4.
Bioorg.Med.Chem.Lett., 25:1836-1841, 2015

PubMed Abstract: Interleukin receptor-associated kinase 4 (IRAK4) is a critical element of the Toll-like/interleukin-1 receptor inflammation signaling pathway. A screening campaign identified a novel diaminopyrimidine hit that exhibits weak IRAK4 inhibitory activity and a ligand efficiency of 0.25. Hit-to-lead activities were conducted through independent SAR studies of each of the four pyrimidine substituents. Optimal activity was observed upon removal of the pyrimidine C-4 chloro substituent. The intact C-6 carboribose is required for IRAK4 inhibition. Numerous heteroaryls were tolerated at the C-5 position, with azabenzothiazoles conferring the best activities. Aminoheteroaryls were preferred at the C-2 position. These studies led to the discovery of inhibitors 35, 36, and 38 that exhibit nanomolar inhibition of IRAK4, improved ligand efficiencies, and modest kinase selectivities.

PubMed: 25870132
DOI: 10.1016/j.bmcl.2015.03.043

Experimental method

X-RAY DIFFRACTION (2.73 Å)