6F3I

IRAK4 IN COMPLEX WITH inhibitor

6F3I の概要

• エントリーDOI: 10.2210/pdb6f3i/pdb
• 分子名称: Interleukin-1 receptor-associated kinase 4, (3~{R})-3-[4-[[4-(4-ethanoylpiperazin-1-yl)cyclohexyl]amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl]butanamide, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: irak4, kinase, inhibitor, cancer, signaling protein
• 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: 2
• 化学式量合計: 74007.31

構造登録者

Xue, Y.,Degorce, S.L.,Robb, G.R.,Ferguson, A.D. (登録日: 2017-11-28, 公開日: 2018-05-23)

主引用文献

Degorce, S.L.,Anjum, R.,Dillman, K.S.,Drew, L.,Groombridge, S.D.,Halsall, C.T.,Lenz, E.M.,Lindsay, N.A.,Mayo, M.F.,Pink, J.H.,Robb, G.R.,Scott, J.S.,Stokes, S.,Xue, Y.
Optimization of permeability in a series of pyrrolotriazine inhibitors of IRAK4.
Bioorg. Med. Chem., 26:913-924, 2018

PubMed Abstract: We have developed a series of orally efficacious IRAK4 inhibitors, based on a scaffold hopping strategy and using rational structure based design. Efforts to tackle low permeability and high efflux in our previously reported pyrrolopyrimidine series (Scott et al., 2017) led to the identification of pyrrolotriazines which contained one less formal hydrogen bond donor and were intrinsically more lipophilic. Further optimisation of substituents on this pyrrolotriazine core culminated with the discovery of 30 as a promising in vivo probe to assess the potential of IRAK4 inhibition for the treatment of MyD88 mutant DLBCL in combination with a BTK inhibitor. When tested in an ABC-DLBCL model with a dual MyD88/CD79 mutation (OCI-LY10), 30 demonstrated tumour regressions in combination with ibrutinib.

PubMed: 29398441
DOI: 10.1016/j.bmc.2018.01.008

実験手法

X-RAY DIFFRACTION (2.14 Å)