5UIS

Crystal structure of IRAK4 in complex with compound 12

Summary for 5UIS

• Entry DOI: 10.2210/pdb5uis/pdb
• Related: 5UIQ 5UIR 5UIT 5UIU
• Descriptor: Interleukin-1 receptor-associated kinase 4, 4-{[(3R)-piperidin-3-yl]oxy}-6-[(propan-2-yl)oxy]quinoline-7-carboxamide (3 entities in total)
• Functional Keywords: transferase, irak4, kinase, fragment screening
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : Q9NWZ3
• Total number of polymer chains: 4
• Total formula weight: 147333.73

Authors

Han, S.,Chang, J.S. (deposition date: 2017-01-14, release date: 2017-05-24, Last modification date: 2024-10-23)

Primary citation

Lee, K.L.,Ambler, C.M.,Anderson, D.R.,Boscoe, B.P.,Bree, A.G.,Brodfuehrer, J.I.,Chang, J.S.,Choi, C.,Chung, S.,Curran, K.J.,Day, J.E.,Dehnhardt, C.M.,Dower, K.,Drozda, S.E.,Frisbie, R.K.,Gavrin, L.K.,Goldberg, J.A.,Han, S.,Hegen, M.,Hepworth, D.,Hope, H.R.,Kamtekar, S.,Kilty, I.C.,Lee, A.,Lin, L.L.,Lovering, F.E.,Lowe, M.D.,Mathias, J.P.,Morgan, H.M.,Murphy, E.A.,Papaioannou, N.,Patny, A.,Pierce, B.S.,Rao, V.R.,Saiah, E.,Samardjiev, I.J.,Samas, B.M.,Shen, M.W.H.,Shin, J.H.,Soutter, H.H.,Strohbach, J.W.,Symanowicz, P.T.,Thomason, J.R.,Trzupek, J.D.,Vargas, R.,Vincent, F.,Yan, J.,Zapf, C.W.,Wright, S.W.
Discovery of Clinical Candidate 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design.
J. Med. Chem., 60:5521-5542, 2017

PubMed Abstract: Through fragment-based drug design focused on engaging the active site of IRAK4 and leveraging three-dimensional topology in a ligand-efficient manner, a micromolar hit identified from a screen of a Pfizer fragment library was optimized to afford IRAK4 inhibitors with nanomolar potency in cellular assays. The medicinal chemistry effort featured the judicious placement of lipophilicity, informed by co-crystal structures with IRAK4 and optimization of ADME properties to deliver clinical candidate PF-06650833 (compound 40). This compound displays a 5-unit increase in lipophilic efficiency from the fragment hit, excellent kinase selectivity, and pharmacokinetic properties suitable for oral administration.

PubMed: 28498658
DOI: 10.1021/acs.jmedchem.7b00231

Experimental method

X-RAY DIFFRACTION (2.5 Å)