6F3I

IRAK4 IN COMPLEX WITH inhibitor

Summary for 6F3I

• Entry DOI: 10.2210/pdb6f3i/pdb
• Descriptor: 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)
• Functional Keywords: irak4, kinase, inhibitor, cancer, signaling protein
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : Q9NWZ3
• Total number of polymer chains: 2
• Total formula weight: 74007.31

Authors

Xue, Y.,Degorce, S.L.,Robb, G.R.,Ferguson, A.D. (deposition date: 2017-11-28, release date: 2018-05-23, Last modification date: 2024-11-13)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.14 Å)