4L7S

Kinase domain mutant of human Itk in complex with an aminobenzothiazole inhibitor

Summary for 4L7S

• Entry DOI: 10.2210/pdb4l7s/pdb
• Related: 4KIO
• Descriptor: Tyrosine-protein kinase ITK/TSK, trans-4-({4-[difluoro(4-fluorophenyl)methyl]-6-[(5-methoxy[1,3]thiazolo[5,4-b]pyridin-2-yl)amino]pyrimidin-2-yl}amino)cyclohexanol, SULFATE ION, ... (4 entities in total)
• Functional Keywords: kinase domain, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q08881
• Total number of polymer chains: 2
• Total formula weight: 61558.13

Authors

Somers, D.O. (deposition date: 2013-06-14, release date: 2014-01-22, Last modification date: 2024-02-28)

Primary citation

Alder, C.M.,Ambler, M.,Campbell, A.J.,Champigny, A.C.,Deakin, A.M.,Harling, J.D.,Harris, C.A.,Longstaff, T.,Lynn, S.,Maxwell, A.C.,Mooney, C.J.,Scullion, C.,Singh, O.M.,Smith, I.E.,Somers, D.O.,Tame, C.J.,Wayne, G.,Wilson, C.,Woolven, J.M.
Identification of a Novel and Selective Series of Itk Inhibitors via a Template-Hopping Strategy.
ACS Med Chem Lett, 4:948-952, 2013

PubMed Abstract: Inhibition of Itk potentially constitutes a novel, nonsteroidal treatment for asthma and other T-cell mediated diseases. In-house kinase cross-screening resulted in the identification of an aminopyrazole-based series of Itk inhibitors. Initial work on this series highlighted selectivity issues with several other kinases, particularly AurA and AurB. A template-hopping strategy was used to identify a series of aminobenzothiazole Itk inhibitors, which utilized an inherently more selective hinge binding motif. Crystallography and modeling were used to rationalize the observed selectivity. Initial exploration of the SAR around this series identified potent Itk inhibitors in both enzyme and cellular assays.

PubMed: 24900590
DOI: 10.1021/ml400206q

Experimental method

X-RAY DIFFRACTION (2.03 Å)