Hit-to-lead studies on benzimidazole inhibitors of ITK: Discovery of a novel class of kinase inhibitors

Snow, Roger J.; Abeywardane, Asitha; Campbell, Scot; Lord, John; Kashem, Mohammed A.; Khine, Hnin Hnin; King, Josephine; Kowalski, Jennifer A.; Pullen, Steven S.; Roma, Teresa; Roth, Gregory P.; Sarko, Christopher R.; Wilson, Noel S.; Winters, Michael P.; Wolak, John P.; Cywin, Charles L.

doi:10.1016/j.bmcl.2007.04.045

Cited by 62 publications

(32 citation statements)

References 19 publications

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“…Our data suggest that by altering signals coming from this kinase one can manipulate these T cell responses. A number of inhibitors have recently been developed that target the kinase activity of Itk, which completely inhibit T cell responses (17)(18)(19)(20)(21), but can potentially lead to immunosuppression. Our work in this study suggests that manipulation of the dose of these inhibitors to selectively alter T cell migration while maintaining normal systemic T cell responses may provide researchers with a better and more effective strategy to treat allergic asthma.…”

Section: Discussionmentioning

confidence: 99%

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Differential Sensitivity to Itk Kinase Signals for T Helper 2 Cytokine Production and Chemokine-Mediated Migration

Sahu

Mueller

Fischer

et al. 2008

The Journal of Immunology

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Allergic asthma is dependent on chemokine-mediated Th2 cell migration and Th2 cytokine secretion into the lungs. The inducible T cell tyrosine kinase Itk regulates the production of Th2 cytokines as well as migration in response to chemokine gradients. Mice lacking Itk are resistant to developing allergic asthma. However, the role of kinase activity of Itk in the development of this disease is unclear. In addition, whether distinct Itk-derived signals lead to T cell migration and secretion of Th2 cytokines is also unknown. Using transgenic mice specifically lacking Itk kinase activity, we show that active kinase signaling is required for control of Th2 responses and development of allergic asthma. Moreover, dominant suppression of kinase Itk activity led to normal Th2 responses, but significantly reduced chemokine-mediated migration, resulting in prevention of allergic asthma. These observations indicate that signals required for Th2 responses and migration are differentially sensitive to Itk activity. Manipulation of Itk’s activity can thus provide a new strategy to treat allergic asthma by differentially affecting migration of T cells into the lungs, leaving Th2 responses intact.

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Section: Discussionmentioning

confidence: 99%

“…Because mice lacking Itk are resistant to developing allergic asthma (6,7), a number of inhibitors have recently been developed that target the kinase activity of Itk (17)(18)(19)(20)(21). However, the role of kinase activity of Itk in the induction of allergic asthma is still unknown.…”

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confidence: 99%

Differential Sensitivity to Itk Kinase Signals for T Helper 2 Cytokine Production and Chemokine-Mediated Migration

Sahu

Mueller

Fischer

et al. 2008

The Journal of Immunology

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“…Therefore, numerous biological activities and functions such as antihelminthic (Mavrova et al, 2005), antifungal (Goker et al, 2002), antiallergic, antimicrobial Andrzejewska et al, 2002;Ozden et al, 2005), antiviral (Ramla et al, 2006), and antineoplastic activity (Starcevic et al, 2007) have been described. They inhibit cyclin dependent kinase or tyrosine kinase and as such are useful for inhibiting cell proliferation in the treatment of cancer (Shugar et al, 1999;Snow et al, 2007;Lemaire et al, 2004). Owing to the important role of amino acids in life processes, new biologically active compounds have been sought for a long time among natural amino acids, their synthetic analogs, and various compounds containing amino-acid fragments.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and cytotoxic evaluation of novel 2-(4-(2,2,2-trifluoroethoxy)-3-methylpyridin-2-ylthio)-1H-benzo[d]imidazole derivatives

et al. 2009

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The present work deals with the anticancer effect of benzimidazole derivatives associated with the pyridine framework. By varying the functional group at N-terminal of the benzimidazole by different L-amino acids, several 2-(4-(2,2,2-trifluoroethoxy)-3-methylpyridin-2-ylthio)-1Hbenzo[d]imidazole derivatives 9(a-j) were synthesized. Their chemical structures were confirmed by (1)H NMR, IR and mass spectroscopic techniques. The synthesized compounds were examined for their antiproliferative effects against human leukemia cell lines, K562 and CEM. The preliminary results showed most of the derivatives had moderate antitumor activity. Compound 9j containing cysteine residue exhibited good inhibition compared to other amino acid resides. In addition DNA fragmentation results suggest that 9j is more cytotoxic and able to induce apoptosis.

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“…There are three distinct classes of non-receptor protein tyrosine kinases, namely Src family kinases (Lck and Lyn), Syk family kinases (ZAP-70 and Syk), and Tec family kinases (Itk, Txk, and Tec). 5 Among these three types, Itk is very important one for its critical activity such as phosporylated Itk required for phosporylation of PLC-γ5 and hence calcium mobilization and activation of downstream pathways. 6 A Gene knockout study reveals that CD4 + T-cells mixed with lymphocyte reaction 7 or upon anti CD3 stimulation, which reduces cytokines IL-2, IL-4, IL-5 and IL-13 production, which leads inflammatory diseases such as rheumatoid arthritis and allergic asthma.…”

Section: Introductionmentioning

confidence: 99%

Pharmacophore Design for Anti-inflammatory Agent Targeting Interleukin-2 Inducible Tyrosine Kinase (Itk)

Meganathan¹,

Thangapandian²,

Sundaraganesan³

et al. 2010

Bulletin of the Korean Chemical Society

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A three dimensional pharmacophore model was generated for the molecules which are responsible for anti-inflammatory activities targeting Interleukin-2 inducible tyrosine kinase (Itk). 16 structurally diverse molecules were selected as training set to generate the hypotheses using Discovery Studio v2.1. The best hypothesis, Hypo1, comprises two hydrogen bond acceptor (HBA), one hydrophobic aromatic (HA), one ring aromatic (RA) and shows high cost difference (63.71), high correlation coefficient (0.97) as well as low RMS deviation (0.81). Hypo1 has been further validated toward a test set, decoy set and Fischer's randomization method. Furthermore, Hypo1 was used to screen NCI and Maybridge databases. Finally, 2 hit molecules were identified as potential leads against Itk, which may be useful for future drug development.

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Hit-to-lead studies on benzimidazole inhibitors of ITK: Discovery of a novel class of kinase inhibitors

Cited by 62 publications

References 19 publications

Differential Sensitivity to Itk Kinase Signals for T Helper 2 Cytokine Production and Chemokine-Mediated Migration

Differential Sensitivity to Itk Kinase Signals for T Helper 2 Cytokine Production and Chemokine-Mediated Migration

Synthesis and cytotoxic evaluation of novel 2-(4-(2,2,2-trifluoroethoxy)-3-methylpyridin-2-ylthio)-1H-benzo[d]imidazole derivatives

Pharmacophore Design for Anti-inflammatory Agent Targeting Interleukin-2 Inducible Tyrosine Kinase (Itk)

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