Targeting IKKβ in Cancer: Challenges and Opportunities for the Therapeutic Utilisation of IKKβ Inhibitors.

Cells
Jack A Prescott, Simon J Cook

Abstract

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.

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Citations

May 12, 2019·International Journal of Molecular Sciences·Marilina García-Aranda, Maximino Redondo
Jun 24, 2020·The Journal of Clinical Investigation·Paarth B DodhiawalaKian-Huat Lim
Aug 5, 2020·The Journal of Clinical Investigation·Enrica Ek TanJohn E Connolly
May 2, 2019·Frontiers in Immunology·Ning SongLinlin Guo
Jul 28, 2020·International Journal of Molecular Sciences·Venkataramanan RamadassVinay Tergaonkar
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Aug 25, 2019·Cancers·Brittney S Harrington, Christina M Annunziata
Feb 6, 2020·Endocrine-related Cancer·Phungern KhongthongJoanne Edwards
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Dec 17, 2020·Frontiers in Immunology·Fabrizio AntonangeliFrancesca Di Rosa
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Mar 7, 2021·International Journal of Molecular Sciences·Shasha YinWenjian Gan
May 13, 2021·Chemical Communications : Chem Comm·John V NapoleonAmarnath Natarajan
Jul 13, 2021·Journal of Orthopaedic Translation·Xian-Fa DuZhao-Min Zheng
Jul 17, 2021·The Biochemical Journal·Jack A PrescottSimon J Cook
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Jan 15, 2022·The Biochemical Journal·Jack A PrescottSimon J Cook

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Methods Mentioned

BETA
X-ray
acetylation
xenograft
ubiquitination

Clinical Trials Mentioned

NCT00883584
NCT01113333
NCT01463488
NCT01511549
NCT01598415
NCT01633645
NCT00280761

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