Targeting IKKβ in Cancer: Challenges and Opportunities for the Therapeutic Utilisation of IKKβ Inhibitors.
Targeting IKKβ in Cancer: Challenges and Opportunities for the Therapeutic Utilisation of IKKβ Inhibitors.
复制标题
靶向IKKβ在癌症中：IKKβ抑制剂治疗利用的挑战和机会。
作者：
Prescott JA;Cook SJ
NF-κB信号转导失调与许多人类炎症性疾病和恶性肿瘤的发病机制有关。因此，NF-κB通路作为药物发现的有吸引力的治疗靶点引起了关注。IKKβ蛋白激酶作为经典NF-κB信号传导的主要可药物化介体，一直是药物开发管道的历史焦点。数千种具有抗IKKβ活性的化合物已被鉴定，其中许多化合物在癌症和炎性疾病的临床前模型中显示出有希望的疗效。然而，迄今为止，与全身性IKKβ抑制相关的严重靶向毒性和其他安全性问题阻碍了任何IKKβ抑制剂的临床批准。本综述将讨论IKKβ抑制剂迄今为止缺乏临床成功的潜在原因，与其治疗用途相关的挑战，未来利用的现实机会，以及抑制NF-κB信号传导的替代策略，这些策略可能克服与IKKβ抑制相关的一些局限性。
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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DOI：
10.1016/j.biocel.2017.12.020
发表时间：
2018-03
期刊：
The international journal of biochemistry & cell biology
影响因子：
--
作者：
Bennett J;Capece D;Begalli F;Verzella D;D'Andrea D;Tornatore L;Franzoso G
通讯作者：
Franzoso G
影响因子：
4.7
作者：
Begalli F;Bennett J;Capece D;Verzella D;D'Andrea D;Tornatore L;Franzoso G
通讯作者：
Franzoso G
影响因子：
7.3
作者：
Anthony NG;Baiget J;Berretta G;Boyd M;Breen D;Edwards J;Gamble C;Gray AI;Harvey AL;Hatziieremia S;Ho KH;Huggan JK;Lang S;Llona-Minguez S;Luo JL;McIntosh K;Paul A;Plevin RJ;Robertson MN;Scott R;Suckling CJ;Sutcliffe OB;Young LC;Mackay SP
通讯作者：
Mackay SP
影响因子：
10.9
作者：
Barnes SE;Wang Y;Chen L;Molinero LL;Gajewski TF;Evaristo C;Alegre ML
通讯作者：
Alegre ML
影响因子：
20.3
作者：
Bianchi, Giada;Oliva, Laura;Cenci, Simone
通讯作者：
Cenci, Simone