Discovery and SAR of 2-amino-5-(thioaryl)thiazoles as potent and selective Itk inhibitors

Das, Jagabandhu; Furch, Joseph A.; Liu, Chunjian; Moquin, Robert V.; Lin, James; Spergel, Steven H.; McIntyre, Kim W.; Shuster, David J.; O'Day, Kathleen; Penhallow, Becky; Hung, Chen Yi; Doweyko, Arthur M.; Kamath, Amrita V.; Zhang, Hongjian; Marathe, Punit; Kanner, Steven B.; Lin, Teng Nan; Dodd, John H.; Barrish, Joel C.; Wityak, John

doi:10.1016/j.bmcl.2006.04.060

Cited by 65 publications

(17 citation statements)

References 13 publications

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“…By screening compound libraries and analyzing structure and activity relationships (SAR), two aminothiazole based molecule inhibitors of ITK, BMS-488516 and BMS-509744, were identified [81-83]. They are ATP competitive inhibitors, indicating their binding to the ATP binding site of the ITK kinase domain.…”

Section: Itk Inhibitorsmentioning

confidence: 99%

Targeting Interleukin-2 Inducible T-Cell Kinase (ITK) in T-Cell Related Diseases

Zhong¹,

Johnson²,

Byrd³

et al. 2014

PDJ

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IL2-inducible T-cell kinase (ITK), a member of the Tec family tyrosine kinases, is the predominant Tec kinase in T cells and natural killer (NK) cells mediating T cell receptor (TCR) and Fc receptor (Fc R) initiated signal transduction. ITK deficiency results in impaired T and NK cell functions, leading to various disorders including malignancies, inflammation, and autoimmune diseases. In this mini-review, the role of ITK in T cell signaling and the development of small molecule inhibitors of ITK for the treatment of T-cell related disorders is examined.

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Section: Itk Inhibitorsmentioning

confidence: 99%

Targeting Interleukin-2 Inducible T-Cell Kinase (ITK) in T-Cell Related Diseases

Zhong¹,

Johnson²,

Byrd³

et al. 2014

PDJ

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“…The enantiomers of 1 and 2 were required with enantiopurities >99.5% as intermediates in the synthesis of IB kinase (IKK) modulators and other pharmaceuticals. [30][31][32][33][34][35][36][37][38][39] …”

Section: Introductionmentioning

confidence: 99%

Enantioselective enzymatic acylation of 1-(3′-bromophenyl)ethylamine

Gill

Das

Patel

2007

Tetrahedron: Asymmetry

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“…Within this set of inhibitors, 59 compounds were labelled as selective when they fulfilled the following requirements: more than 6 data points available for kinases other than Itk, more than 50 % of which correspond to Ki ’s greater than 1 µM and the lowest Ki measured was for Itk. This set included 7 distinct chemical series, including several examples of pyridones and a previously published series of aminothiazole‐based Itk inhibitors 32. An additional set of 23 pyridone‐pyrazines was also selected in order to monitor the performance on a known, selective structural motif that can match the WaterMap site constraint.…”

Section: Resultsmentioning

confidence: 99%

A Role for Hydration in Interleukin‐2 Inducible T Cell Kinase (Itk) Selectivity

Knegtel

Robinson

2011

Molecular Informatics

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The selectivity profile of kinase inhibitors is commonly explained in terms of favourable or unfavourable interactions between the inhibitor and active site residues. In practice residue sequence differences have not always been sufficient to explain observed selectivity profiles. A series of interleukin-2 inducible T cell kinase (Itk, EC 2.7.10.2) inhibitors that achieve selectivity through the introduction of a single nitrogen atom in an aromatic ring has recently been discovered. Structures of these inhibitors bound to Itk showed this nitrogen to be solvent exposed and not involved in any direct interactions with the enzyme. By analysing active site hydration, using the molecular dynamics tool WaterMap, the observed selectivity profile can be explained in terms of the replacement of a thermodynamically unfavourable water molecule by the inhibitor and improved hydration of the bound ligand. The location of this hydration site was successfully used to enrich virtual screening results in their content of selective Itk inhibitors.

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Discovery and SAR of 2-amino-5-(thioaryl)thiazoles as potent and selective Itk inhibitors

Cited by 65 publications

References 13 publications

Targeting Interleukin-2 Inducible T-Cell Kinase (ITK) in T-Cell Related Diseases

Targeting Interleukin-2 Inducible T-Cell Kinase (ITK) in T-Cell Related Diseases

Enantioselective enzymatic acylation of 1-(3′-bromophenyl)ethylamine

A Role for Hydration in Interleukin‐2 Inducible T Cell Kinase (Itk) Selectivity

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