Itk kinase inhibitors: Initial efforts to improve the metabolical stability and the cell activity of the benzimidazole lead

Moriarty, K.J.M.; Winters, Michael P.; Qiao, Lei; Ryan, Declan; DesJarlis, Renee; Robinson, Darius; Cook, Brian N.; Kashem, Mohammed A.; Kaplita, Paul V.; Liu, Lisa H.; Farrell, Thomas M.; Khine, Hnin Hnin; King, Josephine; Pullen, Steven S.; Roth, Gregory P.; Magolda, Ronald L.; Takahashi, Hidenori

doi:10.1016/j.bmcl.2008.09.017

Cited by 25 publications

(12 citation statements)

References 20 publications

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“…A high‐throughput screen campaign of a compound collection by Bristol‐Myers Squibb and Boehringer Ingelheim (Table ) led to the identification of potent ITK inhibitors (Table S2) from a distinct scaffold series of 2‐aminothiazoles and benzimidazoles , respectively. Further development of benzimidazoles have demonstrated selective inhibition of ITK, improved the cellular and functional potency as well as the drug‐like properties, with the 10n and 10o compounds as excellent agents for proof‐of‐concept studies .…”

Section: Introductionmentioning

confidence: 99%

Inhibitors of BTK and ITK: State of the New Drugs for Cancer, Autoimmunity and Inflammatory Diseases

et al. 2013

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BTK and ITK are cytoplasmic tyrosine kinases of crucial importance for B and T cell development, with loss-of-function mutations causing X-linked agammaglobulinemia and susceptibility to severe, frequently lethal, Epstein-Barr virus infection, respectively. Over the last few years, considerable efforts have been made in order to develop small-molecule inhibitors for these kinases to treat lymphocyte malignancies, autoimmunity or allergy/hypersensitivity. The rationale is that even if complete lack of BTK or ITK during development causes severe immunodeficiency, inactivation after birth may result in a less severe phenotype. Moreover, therapy can be transient or only partially block the activity of BTK or ITK. Furthermore, a drug-induced B cell deficiency is treatable by gamma globulin substitution therapy. The newly developed BTK inhibitor PCI-32765, recently renamed Ibrutinib, has already entered several clinical trials for various forms of non-Hodgkin lymphoma as well as for multiple myeloma. Experimental animal studies have demonstrated highly promising treatment effects also in autoimmunity. ITK inhibitors are still under the early developmental phase, but it can be expected that such drugs will also become very useful. In this study, we present BTK and ITK with their signalling pathways and review the development of the corresponding inhibitors.

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Section: Introductionmentioning

confidence: 99%

Inhibitors of BTK and ITK: State of the New Drugs for Cancer, Autoimmunity and Inflammatory Diseases

et al. 2013

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“…When we started to collect the data, we also saw the early literatures of this group. Considering the distribution of molecules' activities in the different literatures, we selected the dataset in the recent four articles with relatively higher activities compared to the dataset in the early documents . Finally, the dataset in the recent four articles were used to develop the 3D‐QSAR models in this work.…”

Section: Methodsmentioning

confidence: 99%

“…Prior to docking process, we examined and studied carefully all the literatures about ITK inhibitors, and found that a total of 16 articles have done molecular dockings . Water‐mediated hydrogen bonds are reported to play a crucial role in the stabilization of the ligand at the active site .…”

Section: Methodsmentioning

confidence: 99%

Insight into the structural requirements of benzimidazole derivatives as interleukin‐2 inducible t‐cell kinase inhibitors by computational explorations

Wang

et al. 2013

Int J of Quantum Chemistry

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In the present work, a set of ligand-and receptor-based 3D-QSAR models were developed to explore the structure-activity relationship of 109 benzimidazole-based interleukin-2-inducible T-cell kinase (ITK) inhibitors. In order to reveal the requisite 3D structural features impacting the biological activities, a variety of in silico modeling approaches including the comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), docking, and molecular dynamics were applied. The results showed that the ligand-based CoMFA model (Q 2 5 0.552, R IntroductionT cell, also known as T lymphocyte, is a type of white blood cell that is of key importance to the immune system. [1] T-cell plays a central role in cell-mediated immunity which can be found in nearly any tissue at any time. By the presence of a Tcell antigen receptor (TCR) on the cell surface, T-cells are distinguished from other lymphocytes like the B cells and natural killer cells (NK cells), but are most concentrated in the lymphoid organs.[1] The activation of T-cell is critical for the initiation and regulation of the immune response, which leads to the development of cell-mediated immune mechanisms through the action of cytotoxic T-cell as well as by the engagement of accessory cells including macrophages.[2]To activate T-cell, the recognition of TCR is a necessity [3] that it leads to the fast recruitment and activation of three kinds of nonreceptor tyrosine kinases, the Src, Syk, and Tec families. [4] Among the Tec family, the interleukin-2-inducible Tcell kinase (ITK), a nonreceptor tyrosine kinase expressed primarily in hematopoietic cells, serves as an important mediator of antigen receptor signaling in lymphocytes. [2] For ITK, significant attention has been given to its activation via TCR stimulation. Once activated, ITK undergoes cis autophosphorylation on Y180 in its SH3 domain, [2] and plays an important role in Tcell signaling and the production of various pro-inflammatory cytokines such as IL-2, IL-4, IL-5, IL-10, and IL-13. [5] Moreover, ITK has been shown to play an essential role in the development of T cell dependent late phase responses of allergic asthma. [6] In research with ITK deficient mice reduced lung inflammation, mucous production and airway hyper responsiveness were observed in an ovalbumin-induced allergic asthma model. [7] Similar results were reported with a selective ITK inhibitor, which indicated the important role of ITK kinase activity in inflammatory diseases. [8] Therefore, tyrosine kinase ITK is regarded as a promising and an excellent potential therapeutic target for T cell-mediated diseases. The earliest report of selective ITK inhibitors came from researchers at Bristol-Myers Squibb.[5] These inhibitors have been tested in vitro on the human Jurkat T cell line and shown to specifically inhibit ITK and block the tyrosine phosphorylation and activation of phospholipase-Cc1. [9] Although these inhibitors come in handy, more studies are needed to test their efficacy, stability, and ...

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“…Moriarty 76 and co-workers have replaced the 2-thiophene with other heterocyclic moieties, viz. 2-furyl, 5-isoxazole, 3-pyridyl, 4-pyridyl or meta and para substituted phenyl, resulting in an improvement in the activity against ITK (72).…”

Section: Interleukin-2 Inducible T-cell Kinase (Itk) Inhibitorsmentioning

confidence: 99%

Benzimidazole-biologically attractive scaffold for protein kinase inhibitors

2014

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Great advances in elucidating molecular structures allow the precise determination of the interactions between a protein and a therapeutic agent. Enzyme inhibitors are used as a therapeutic agent with organic molecules, that interact with their targets through the weak linkages of hydrogen bonding and van der Waals interactions. These reduce the undesirable side effects and allow more non-specific interactions with non-target molecules. Benzimidazole acts as an enzyme inhibitor that may interact with different proteins and enzymes and has inspired chemists to carry out various structural variations of it. This review discusses the development of distinct benzimidazoles with an array of enzyme inhibitors viz., aurora kinase inhibitors, cyclin-dependent kinase inhibitors, mitogen activated protein kinase inhibitors, polo like kinase inhibitors, Tie kinase inhibitors, lymphocyte specific kinase inhibitors etc., also highlighting the molecular interaction with enzyme inhibitors. Various derivatives of benzimidazole, with different inhibitory activities, have been described on the basis of substitution around the central moiety, with an aim to help medicinal chemists to develop structure-activity relationships. The reviews in the literature till now are focused only on the biological activities of benzimidazole viz., antiviral, anticancer and antifungal, but the present review focuses on the latest work, describing the inhibitor aspects and the potential of the benzimidazole ring. This discussion will further help in the development of novel benzimidazole compounds.

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Itk kinase inhibitors: Initial efforts to improve the metabolical stability and the cell activity of the benzimidazole lead

Cited by 25 publications

References 20 publications

Inhibitors of BTK and ITK: State of the New Drugs for Cancer, Autoimmunity and Inflammatory Diseases

Inhibitors of BTK and ITK: State of the New Drugs for Cancer, Autoimmunity and Inflammatory Diseases

Insight into the structural requirements of benzimidazole derivatives as interleukin‐2 inducible t‐cell kinase inhibitors by computational explorations

Benzimidazole-biologically attractive scaffold for protein kinase inhibitors

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