4RFM

ITK kinase domain in complex with compound 1 N-{1-[(1,1-dioxo-1-thian-2-yl)(phenyl)methyl]-1H- pyrazol-4-yl}-5,5-difluoro-5a-methyl-1H,4H,4aH,5H,5aH,6H-cyclopropa[f]indazole-3-carboxamide

Summary for 4RFM

• Entry DOI: 10.2210/pdb4rfm/pdb
• Descriptor: Tyrosine-protein kinase ITK/TSK, (4aS,5aR)-N-{1-[(R)-[(2R)-1,1-dioxidotetrahydro-2H-thiopyran-2-yl](phenyl)methyl]-1H-pyrazol-4-yl}-5,5-difluoro-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3-carboxamide (3 entities in total)
• Functional Keywords: kinase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : Q08881
• Total number of polymer chains: 1
• Total formula weight: 30631.99

Authors

McEwan, P.A.,Barker, J.J.,Eigenbrot, C. (deposition date: 2014-09-26, release date: 2015-04-29, Last modification date: 2024-02-28)

Primary citation

Burch, J.D.,Barrett, K.,Chen, Y.,DeVoss, J.,Eigenbrot, C.,Goldsmith, R.,Ismaili, M.H.,Lau, K.,Lin, Z.,Ortwine, D.F.,Zarrin, A.A.,McEwan, P.A.,Barker, J.J.,Ellebrandt, C.,Kordt, D.,Stein, D.B.,Wang, X.,Chen, Y.,Hu, B.,Xu, X.,Yuen, P.W.,Zhang, Y.,Pei, Z.
Tetrahydroindazoles as Interleukin-2 Inducible T-Cell Kinase Inhibitors. Part II. Second-Generation Analogues with Enhanced Potency, Selectivity, and Pharmacodynamic Modulation in Vivo.
J.Med.Chem., 58:3806-3816, 2015

PubMed Abstract: The medicinal chemistry community has directed considerable efforts toward the discovery of selective inhibitors of interleukin-2 inducible T-cell kinase (ITK), given its role in T-cell signaling downstream of the T-cell receptor (TCR) and the implications of this target for inflammatory disorders such as asthma. We have previously disclosed a structure- and property-guided lead optimization effort which resulted in the discovery of a new series of tetrahydroindazole-containing selective ITK inhibitors. Herein we disclose further optimization of this series that resulted in further potency improvements, reduced off-target receptor binding liabilities, and reduced cytotoxicity. Specifically, we have identified a correlation between the basicity of solubilizing elements in the ITK inhibitors and off-target antiproliferative effects, which was exploited to reduce cytotoxicity while maintaining kinase selectivity. Optimized analogues were shown to reduce IL-2 and IL-13 production in vivo following oral or intraperitoneal dosing in mice.

PubMed: 25844760
DOI: 10.1021/jm501998m

Experimental method

X-RAY DIFFRACTION (2.1 Å)