Targeting IKKβ in Cancer: Challenges and Opportunities for the Therapeutic Utilisation of IKKβ Inhibitors
Deregulated NF-κB signalling is implicated in the pathogenesis of numerous human inflammatory disorders and malignancies. Consequently, the NF-κB pathway has attracted attention as an attractive therapeutic target for drug discovery. As the primary, druggable mediator of canonica...
| Main Authors: | , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2018-08-01
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| Series: | Cells |
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| Online Access: | http://www.mdpi.com/2073-4409/7/9/115 |
| _version_ | 1827838593909915648 |
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| author | Jack A. Prescott Simon J. Cook |
| author_facet | Jack A. Prescott Simon J. Cook |
| author_sort | Jack A. Prescott |
| collection | DOAJ |
| description | Deregulated NF-κB signalling is implicated in the pathogenesis of numerous human inflammatory disorders and malignancies. Consequently, the NF-κB pathway has attracted attention as an attractive therapeutic target for drug discovery. As the primary, druggable mediator of canonical NF-κB signalling the IKKβ protein kinase has been the historical focus of drug development pipelines. Thousands of compounds with activity against IKKβ have been characterised, with many demonstrating promising efficacy in pre-clinical models of cancer and inflammatory disease. However, severe on-target toxicities and other safety concerns associated with systemic IKKβ inhibition have thus far prevented the clinical approval of any IKKβ inhibitors. This review will discuss the potential reasons for the lack of clinical success of IKKβ inhibitors to date, the challenges associated with their therapeutic use, realistic opportunities for their future utilisation, and the alternative strategies to inhibit NF-κB signalling that may overcome some of the limitations associated with IKKβ inhibition. |
| first_indexed | 2024-03-12T07:08:08Z |
| format | Article |
| id | doaj.art-68a8495535e74b82ac3f689ef4605eb2 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T07:08:08Z |
| publishDate | 2018-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-68a8495535e74b82ac3f689ef4605eb22023-09-02T23:18:56ZengMDPI AGCells2073-44092018-08-017911510.3390/cells7090115cells7090115Targeting IKKβ in Cancer: Challenges and Opportunities for the Therapeutic Utilisation of IKKβ InhibitorsJack A. Prescott0Simon J. Cook1Signalling Laboratory, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UKSignalling Laboratory, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UKDeregulated NF-κB signalling is implicated in the pathogenesis of numerous human inflammatory disorders and malignancies. Consequently, the NF-κB pathway has attracted attention as an attractive therapeutic target for drug discovery. As the primary, druggable mediator of canonical NF-κB signalling the IKKβ protein kinase has been the historical focus of drug development pipelines. Thousands of compounds with activity against IKKβ have been characterised, with many demonstrating promising efficacy in pre-clinical models of cancer and inflammatory disease. However, severe on-target toxicities and other safety concerns associated with systemic IKKβ inhibition have thus far prevented the clinical approval of any IKKβ inhibitors. This review will discuss the potential reasons for the lack of clinical success of IKKβ inhibitors to date, the challenges associated with their therapeutic use, realistic opportunities for their future utilisation, and the alternative strategies to inhibit NF-κB signalling that may overcome some of the limitations associated with IKKβ inhibition.http://www.mdpi.com/2073-4409/7/9/115IKKinhibitory kappa B kinasenuclear factor kappa Binflammationcancersmall molecule kinase inhibitorstherapeutics |
| spellingShingle | Jack A. Prescott Simon J. Cook Targeting IKKβ in Cancer: Challenges and Opportunities for the Therapeutic Utilisation of IKKβ Inhibitors Cells IKK inhibitory kappa B kinase nuclear factor kappa B inflammation cancer small molecule kinase inhibitors therapeutics |
| title | Targeting IKKβ in Cancer: Challenges and Opportunities for the Therapeutic Utilisation of IKKβ Inhibitors |
| title_full | Targeting IKKβ in Cancer: Challenges and Opportunities for the Therapeutic Utilisation of IKKβ Inhibitors |
| title_fullStr | Targeting IKKβ in Cancer: Challenges and Opportunities for the Therapeutic Utilisation of IKKβ Inhibitors |
| title_full_unstemmed | Targeting IKKβ in Cancer: Challenges and Opportunities for the Therapeutic Utilisation of IKKβ Inhibitors |
| title_short | Targeting IKKβ in Cancer: Challenges and Opportunities for the Therapeutic Utilisation of IKKβ Inhibitors |
| title_sort | targeting ikkβ in cancer challenges and opportunities for the therapeutic utilisation of ikkβ inhibitors |
| topic | IKK inhibitory kappa B kinase nuclear factor kappa B inflammation cancer small molecule kinase inhibitors therapeutics |
| url | http://www.mdpi.com/2073-4409/7/9/115 |
| work_keys_str_mv | AT jackaprescott targetingikkbincancerchallengesandopportunitiesforthetherapeuticutilisationofikkbinhibitors AT simonjcook targetingikkbincancerchallengesandopportunitiesforthetherapeuticutilisationofikkbinhibitors |