Discovery of potent inhibitors of interleukin-2 inducible T-cell kinase (ITK) through structure-based drug design

doi:10.1016/j.bmcl.2008.12.028

Bioorganic & Medicinal Chemistry Letters

Volume 19, Issue 3, 1 February 2009, Pages 773-777

https://doi.org/10.1016/j.bmcl.2008.12.028 Get rights and content

Abstract

Interleukin-2 inducible T-cell kinase (ITK) is a member of the Tec kinase family and is involved with T-cell activation and proliferation. Due to its critical role in acting as a modulator of T-cells, ITK inhibitors could provide a novel route to anti-inflammatory therapy. This work describes the discovery of ITK inhibitors through structure-based design where high-resolution crystal structural information was used to optimize interactions within the kinase specificity pocket of the enzyme to improve both potency and selectivity.

Graphical abstract

This work describes the discovery of ITK inhibitors through structure-based design where high-resolution crystal structural information was used to optimize interactions within the kinase specificity pocket of the enzyme to improve both potency and selectivity.

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IL-2 Itk also has an aberrant role in inflammatory disorders like lung inflammation, skin dermatitis, and asthma and HIV infections [8,9]. Itk inhibitors reported in literature are 2 amino 5 [(thiomethyl)aryl] thiazoles [10], 2 amino 5 (thioaryl) thiazoles [11], 4/5 arylpyrazolyl indoles [12], benzimidazole derivatives [13–17] and pyrazolopyrimidines [18]. This detailed information of chemical features that can positively enhance the biological activity of inhibitor is considered to be important to design new potent compounds.
In the current study, quantitative three-dimensional structure-activity-relationship (3D-QSAR) method was performed to design a model for new chemical entities by utilizing pyrazolopyrimidines. Their inhibiting activity on receptor IL-2 Itk correlates descriptors based on topology and hydrophobicity. The best model developed by ligand-based (atom-based) approach has correlation-coefficient of r²: 0.987 and cross-validated squared correlation-coefficient of q²: 0.541 with an external prediction capability of r²: 0.944. Whereas the best selected model developed by structured-based (receptor-based) approach has correlation-coefficient of r²: 0.987, cross-validated squared correlation-coefficient of q²: 0.637 with an external predictive ability of r²: 0.941. The statistical parameters prove that structure-based gave a better model to design new chemical scaffolds. The results achieved indicated that hydrophobicity at R₁ location play a vital role in the inhibitory activity and introduction of appropriately bulky and strongly hydrophobic-groups at position 3 of the terminal phenyl-group which is highly significant to enhance the activity. Six new pyrazolopyrimidine derivatives were designed. Docking simulation study was carried out and their inhibitory activity was predicted by the best structure based model with predictive activity of ranging from 8.43 to 8.85 log unit. The interacting residues PHE435, ASP500, LYS391, GLU436, MET438, CYS442, ILE369, VAL377 of PDB 4HCT were studied with respect to type of bonding with the new compounds. This study was aimed to search out more potent inhibitors of IL-2 Itk.
Inhibitors of interleukin-2 inducible T-cell kinase as potential therapeutic candidates for the treatment of various inflammatory disease conditions
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Large sized groups are unfavorable due to steric clashes with active site amino acids of protein (cpd. 48) (Cook et al., 2009; Lo et al., 2008a,b; Moriarty et al., 2008a,b; Snow et al., 2007; Winters et al., 2008; WO2007076228). The reported docking studies of benzimidazole derivatives (cpd.
Interleukin-2 inducible T-cell kinase (ITK), a member of Tec family of non-receptor protein tyrosine kinases plays a domineering role in the T-cell development, differentiation and production of pro-inflammatory cytokines such as IL-2, IL-4, IL-5, IL-10, IL-13 and IL-17. This kinase is also an important contributor in Th 2 cells mediated autoimmune and allergic disease conditions, e.g. psoriasis, atopic dermatitis and allergic asthma. ITK modulates T-cell signaling by activating PLCγ1 and regulating the extent of Ca²⁺ flux. It contributes in prolific T-cell responses by maintaining cellular adhesion and cytoskeleton reorganization via actin polymerization and integrin binding. This review article describes the structure of ITK and its role in T-cell signaling. In addition to this, data regarding small molecule inhibitors of ITK has also been reviewed from different papers and patents published.
X-ray crystallographic structure-based design of selective thienopyrazole inhibitors for interleukin-2-inducible tyrosine kinase
2012, Bioorganic and Medicinal Chemistry Letters
Beginning with a screening hit, unique thienopyrazole-indole inhibitors of Itk (interleukin-2-inducible tyrosine kinase) were designed, synthesized, and crystallized in the target kinase. Although initial compounds were highly active in Itk, they were not selective. Increasing the steric bulk around a tertiary alcohol at the 5-indole position dramatically improved selectivity toward Lyk and Syk, but not Txk. Substitutions at the 3- and 4-indole positions gave less active compounds that remained poorly selective. A difluoromethyl substitution at the 5-position of the thienopyrazole led to a highly potent and selective compound. Phenyl at this position reduced activity and selectivity while pushing the side-chains of Lys-391 and Asp-500 away from the binding pocket. Novel and selective thienopyrazole inhibitors of Itk were designed as a result of combining structure-based design and medicinal chemistry.
Identification of potent ITK inhibitors through focused compound library design including structural information
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A series of novel compound libraries inhibiting interleukin-2 inducible T cell kinase (ITK) were designed, synthesized and evaluated. In the first design cycle two library scaffolds were identified showing low micromolar inhibition of ITK. Further iterative design cycles including crystal structure information of ITK and structurally related kinases led to the identification of indolylindazole and indolylpyrazolopyridine compounds with low nanomolar ITK inhibition.
Synthesis and biological evaluation of novel (4 or 5-aryl)pyrazolyl-indoles as inhibitors of interleukin-2 inducible T-cell kinase (ITK)
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Interleukin-2 inducible T-cell kinase (ITK) is one of five kinases that belong to the Tec kinase family that plays an important role in T-cell and mast cell signaling. Various reports point to a role of ITK in the treatment of allergic asthma. For example, it was shown that mice lacking ITK have reduced airway hyperresponsiveness, inflammation and tracheal responses in an allergic asthma model. In this article, we disclose novel ITK inhibitors based on (4 or 5-aryl)pyrazolyl-indole scaffold that were also found to be selective for ITK over other kinases like IRK, CDK2, GSK3ß and PKA.

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^†: Present address: Burnham Institute for Medical Research at Lake Nona, Orlando, FL 32819, USA.

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Discovery of potent inhibitors of interleukin-2 inducible T-cell kinase (ITK) through structure-based drug design

Abstract

Graphical abstract

Curr. Opin. Immunol.

Annu. Rev. Immunol.

Nat. Rev. Immunol.

Bioorg. Med. Chem. Lett.

Curr. Med. Chem.

Curr. Top. Med. Chem.

J. Med. Chem.

Biochemistry

Nat. Immunol.