4PQN

ITK kinase domain with compound GNE-9822

Summary for 4PQN

• Entry DOI: 10.2210/pdb4pqn/pdb
• Descriptor: Tyrosine-protein kinase ITK/TSK, N-{1-[(1S)-3-(dimethylamino)-1-phenylpropyl]-1H-pyrazol-4-yl}-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide, 1-ETHOXY-2-(2-ETHOXYETHOXY)ETHANE, ... (4 entities in total)
• Functional Keywords: protein kinase, phospho-transfer, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q08881
• Total number of polymer chains: 1
• Total formula weight: 30699.19

Authors

McEwan, P.A.,Barker, J.J.,Eigenbrot, C. (deposition date: 2014-03-03, release date: 2014-07-02, Last modification date: 2023-09-20)

Primary citation

Burch, J.D.,Lau, K.,Barker, J.J.,Brookfield, F.,Chen, Y.,Chen, Y.,Eigenbrot, C.,Ellebrandt, C.,Ismaili, M.H.,Johnson, A.,Kordt, D.,MacKinnon, C.H.,McEwan, P.A.,Ortwine, D.F.,Stein, D.B.,Wang, X.,Winkler, D.,Yuen, P.W.,Zhang, Y.,Zarrin, A.A.,Pei, Z.
Property- and structure-guided discovery of a tetrahydroindazole series of interleukin-2 inducible T-cell kinase inhibitors.
J.Med.Chem., 57:5714-5727, 2014

PubMed Abstract: Interleukin-2 inducible T-cell kinase (ITK), a member of the Tec family of tyrosine kinases, plays a major role in T-cell signaling downstream of the T-cell receptor (TCR), and considerable efforts have been directed toward discovery of ITK-selective inhibitors as potential treatments of inflammatory disorders such as asthma. Using a previously disclosed indazole series of inhibitors as a starting point, and using X-ray crystallography and solubility forecast index (SFI) as guides, we evolved a series of tetrahydroindazole inhibitors with improved potency, selectivity, and pharmaceutical properties. Highlights include identification of a selectivity pocket above the ligand plane, and identification of appropriate lipophilic substituents to occupy this space. This effort culminated in identification of a potent and selective ITK inhibitor (GNE-9822) with good ADME properties in preclinical species.

PubMed: 24918870
DOI: 10.1021/jm500550e

Experimental method

X-RAY DIFFRACTION (1.71 Å)