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Literature DB >> 17499505

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

Roger J Snow¹, Asitha Abeywardane, Scot Campbell, John Lord, Mohammed A Kashem, Hnin Hnin Khine, Josephine King, Jennifer A Kowalski, Steven S Pullen, Teresa Roma, Gregory P Roth, Christopher R Sarko, Noel S Wilson, Michael P Winters, John P Wolak, Charles L Cywin.

Abstract

Benzimidazole 1 was identified as a selective inhibitor of ITK by high throughput screening. Hit-to-lead studies defined the SAR at all three substituents. Reversing the amide linkage at C6 led to 16, with a fivefold improvement of potency. This enhancement is rationalized by the conformational preference of the substituent. A model for the binding of the benzimidazoles to the ATP-binding site of ITK is proposed.

Entities: Chemical Gene

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Year: 2007 PMID： 17499505 DOI： 10.1016/j.bmcl.2007.04.045

Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823

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Cited

13 in total

1. A Small Molecule Inhibitor of ITK and RLK Impairs Th1 Differentiation and Prevents Colitis Disease Progression.

Authors: Hyoung-Soo Cho; Hyun Mu Shin; Helena Haberstock-Debic; Yan Xing; Timothy D Owens; Jens Oliver Funk; Ronald J Hill; J Michael Bradshaw; Leslie J Berg
Journal: J Immunol Date: 2015-10-14 Impact factor: 5.422

2. Conventional and microwave-assisted synthesis of new indole-tethered benzimidazole-based 1,2,3-triazoles and evaluation of their antimycobacterial, antioxidant and antimicrobial activities.

Authors: Dongamanti Ashok; Srinivas Gundu; Vikas Kumar Aamate; Mohan Gandhi Devulapally
Journal: Mol Divers Date: 2018-04-18 Impact factor: 2.943

3. Discovery of potent inhibitors for interleukin-2-inducible T-cell kinase: structure-based virtual screening and molecular dynamics simulation approaches.

Authors: Chandrasekaran Meganathan; Sugunadevi Sakkiah; Yuno Lee; Jayavelu Venkat Narayanan; Keun Woo Lee
Journal: J Mol Model Date: 2012-09-27 Impact factor: 1.810

4. Targeting interleukin-2-inducible T-cell kinase (ITK) and resting lymphocyte kinase (RLK) using a novel covalent inhibitor PRN694.

Authors: Yiming Zhong; Shuai Dong; Ethan Strattan; Li Ren; Jonathan P Butchar; Kelsey Thornton; Anjali Mishra; Pierluigi Porcu; J Michael Bradshaw; Angelina Bisconte; Timothy D Owens; Erik Verner; Ken A Brameld; Jens Oliver Funk; Ronald J Hill; Amy J Johnson; Jason A Dubovsky
Journal: J Biol Chem Date: 2015-01-15 Impact factor: 5.157

10. TEC and MAPK Kinase Signalling Pathways in T helper (T_H) cell Development, T_H2 Differentiation and Allergic Asthma.

Authors: Yashaswini Kannan; Mark S Wilson
Journal: J Clin Cell Immunol Date: 2012

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

1. A Small Molecule Inhibitor of ITK and RLK Impairs Th1 Differentiation and Prevents Colitis Disease Progression.

2. Conventional and microwave-assisted synthesis of new indole-tethered benzimidazole-based 1,2,3-triazoles and evaluation of their antimycobacterial, antioxidant and antimicrobial activities.

3. Discovery of potent inhibitors for interleukin-2-inducible T-cell kinase: structure-based virtual screening and molecular dynamics simulation approaches.

4. Targeting interleukin-2-inducible T-cell kinase (ITK) and resting lymphocyte kinase (RLK) using a novel covalent inhibitor PRN694.

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

Review 6. Tec kinases regulate T-lymphocyte development and function: new insights into the roles of Itk and Rlk/Txk.

7. Ethyl 1-sec-butyl-2-(2-hydroxy-phen-yl)-1H-benzimidazole-5-carboxyl-ate 0.25-hydrate.

Review 8. ITK inhibitors in inflammation and immune-mediated disorders.

9. Differential sensitivity to Itk kinase signals for T helper 2 cytokine production and chemokine-mediated migration.

10. TEC and MAPK Kinase Signalling Pathways in T helper (T_H) cell Development, T_H2 Differentiation and Allergic Asthma.