5K75

IRAK4 in complex with Compound 1

Summary for 5K75

• Entry DOI: 10.2210/pdb5k75/pdb
• Related: 5K72 5K76 5K7G 5K7I
• Descriptor: Interleukin-1 receptor-associated kinase 4, ~{N}1-(7,8-dihydro-6~{H}-cyclopenta[2,3]thieno[2,4-~{c}]pyrimidin-1-yl)-~{N}4,~{N}4-dimethyl-cyclohexane-1,4-diamine, SULFATE ION, ... (4 entities in total)
• Functional Keywords: inhibitor, kinase, protein tyrosine kinase, 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: 137443.16

Authors

Ferguson, A.D. (deposition date: 2016-05-25, release date: 2017-12-06, Last modification date: 2024-10-09)

Primary citation

Scott, J.S.,Degorce, S.L.,Anjum, R.,Culshaw, J.,Davies, R.D.M.,Davies, N.L.,Dillman, K.S.,Dowling, J.E.,Drew, L.,Ferguson, A.D.,Groombridge, S.D.,Halsall, C.T.,Hudson, J.A.,Lamont, S.,Lindsay, N.A.,Marden, S.K.,Mayo, M.F.,Pease, J.E.,Perkins, D.R.,Pink, J.H.,Robb, G.R.,Rosen, A.,Shen, M.,McWhirter, C.,Wu, D.
Discovery and Optimization of Pyrrolopyrimidine Inhibitors of Interleukin-1 Receptor Associated Kinase 4 (IRAK4) for the Treatment of Mutant MYD88L265P Diffuse Large B-Cell Lymphoma.
J. Med. Chem., 60:10071-10091, 2017

PubMed Abstract: Herein we report the optimization of a series of pyrrolopyrimidine inhibitors of interleukin-1 receptor associated kinase 4 (IRAK4) using X-ray crystal structures and structure based design to identify and optimize our scaffold. Compound 28 demonstrated a favorable physicochemical and kinase selectivity profile and was identified as a promising in vivo tool with which to explore the role of IRAK4 inhibition in the treatment of mutant MYD88 diffuse large B-cell lymphoma (DLBCL). Compound 28 was shown to be capable of demonstrating inhibition of NF-κB activation and growth of the ABC subtype of DLBCL cell lines in vitro at high concentrations but showed greater effects in combination with a BTK inhibitor at lower concentrations. In vivo, the combination of compound 28 and ibrutinib led to tumor regression in an ABC-DLBCL mouse model.

PubMed: 29172502
DOI: 10.1021/acs.jmedchem.7b01290

Experimental method

X-RAY DIFFRACTION (2.03 Å)