3QGW

Crystal Structure of ITK kinase bound to an inhibitor

Summary for 3QGW

• Entry DOI: 10.2210/pdb3qgw/pdb
• Related: 1SM2 1SNU 1SNX
• Descriptor: Tyrosine-protein kinase ITK/TSK, 3-[(8-phenylthieno[2,3-h]quinazolin-2-yl)amino]benzenesulfonamide, N-(6-oxo-1,6-dihydro-3,4'-bipyridin-5-yl)benzamide, ... (4 entities in total)
• Functional Keywords: protein kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cell membrane (By similarity): Q08881
• Total number of polymer chains: 2
• Total formula weight: 65712.00

Authors

Brown, K.,Cheetham, G.M.T. (deposition date: 2011-01-25, release date: 2011-06-22, Last modification date: 2024-03-20)

Primary citation

Charrier, J.D.,Miller, A.,Kay, D.P.,Brenchley, G.,Twin, H.C.,Collier, P.N.,Ramaya, S.,Keily, S.B.,Durrant, S.J.,Knegtel, R.M.,Tanner, A.J.,Brown, K.,Curnock, A.P.,Jimenez, J.M.
Discovery and structure-activity relationship of 3-aminopyrid-2-ones as potent and selective interleukin-2 inducible T-cell kinase (Itk) inhibitors
J.Med.Chem., 54:2341-2350, 2011

PubMed Abstract: Interleukin-2 inducible T-cell kinase (Itk) plays a role in T-cell functions, and its inhibition potentially represents an attractive intervention point to treat autoimmune and allergic diseases. Herein we describe the discovery of a series of potent and selective novel inhibitors of Itk. These inhibitors were identified by structure-based design, starting from a fragment generated de novo, the 3-aminopyrid-2-one motif. Functionalization of the 3-amino group enabled rapid enhancement of the inhibitory activity against Itk, while introduction of a substituted heteroaromatic ring in position 5 of the pyridone fragment was key to achieving optimal selectivity over related kinases. A careful analysis of the hydration patterns in the kinase active site was necessary to fully explain the observed selectivity profile. The best molecule prepared in this optimization campaign, 7v, inhibits Itk with a K(i) of 7 nM and has a good selectivity profile across kinases.

PubMed: 21391610
DOI: 10.1021/jm101499u

Experimental method

X-RAY DIFFRACTION (2.1 Å)