8DKS

IRAK4 IN COMPLEX WITH COMPOUND #3

Summary for 8DKS

• Entry DOI: 10.2210/pdb8dks/pdb
• Descriptor: Interleukin-1 receptor-associated kinase 4, (1S,2S,3R,4R)-3-({2-[3-(pyrrolidine-1-carbonyl)anilino]thieno[3,2-d]pyrimidin-4-yl}amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide, BETA-MERCAPTOETHANOL, ... (4 entities in total)
• Functional Keywords: kinase inhibitor, irak4, pyrimidine, atp binding, protein binding, signaling protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 104444.48

Authors

Chen, Y.,Lin, N. (deposition date: 2022-07-06, release date: 2022-08-03, Last modification date: 2022-08-17)

Primary citation

Chen, Y.,Tso, K.,Heckrodt, T.J.,Li, H.,Yen, R.,Lin, N.,Singh, R.,Taylor, V.,Masuda, E.S.,Park, G.,Payan, D.G.
Bicyclic pyrimidine compounds as potent IRAK4 inhibitors.
Bioorg.Med.Chem.Lett., 73:128900-128900, 2022

PubMed Abstract: Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role in transduction of IL-1R/TLR signaling which is responsible for innate immune response. From HTS campaign, bicyclic-pyrimidine compounds have been identified as potent IRAK4 inhibitors, exhibiting good potency in both IRAK4 biochemical and LPS induced IL-23 inhibition cell-based assays. The SAR efforts were focused on further improving on-target potency, reducing PAD activities of HTS hit molecule and improving in vivo PK profiles of early lead compounds. When different aromatic rings were fused to the pyrimidine core, and with various substituents at 2- or 4-position of the pyrimidine, the impact on potency and PK properties were observed and are discussed. Selected compounds were further evaluated in IL-1β induced IL-6 inhibition acute animal model and rodent arthritis disease model, of which compounds 33 and 39 showed good efficacy in both studies.

PubMed: 35863718
DOI: 10.1016/j.bmcl.2022.128900

Experimental method

X-RAY DIFFRACTION (2.45 Å)