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

Jack Prescott; Simon Cook

doi:10.3390/cells7090115

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

Cells ◽

10.3390/cells7090115 ◽

2018 ◽

Vol 7 (9) ◽

pp. 115 ◽

Cited By ~ 28

Author(s):

Jack Prescott ◽

Simon Cook

Keyword(s):

Drug Discovery ◽

Protein Kinase ◽

Drug Development ◽

Inflammatory Disease ◽

Therapeutic Target ◽

Clinical Success ◽

Alternative Strategies ◽

Challenges And Opportunities ◽

Attractive Therapeutic Target ◽

Clinical Models

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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AMP-activated protein kinase: An attractive therapeutic target for ischemia-reperfusion injury

European Journal of Pharmacology ◽

10.1016/j.ejphar.2020.173484 ◽

2020 ◽

Vol 888 ◽

pp. 173484

Author(s):

Rong Ding ◽

Wei Wu ◽

Zhou Sun ◽

Zhi Li

Keyword(s):

Protein Kinase ◽

Reperfusion Injury ◽

Therapeutic Target ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Attractive Therapeutic Target ◽

Amp Activated Protein Kinase

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Emerging Role of the NLRP3 Inflammasome and Interleukin-1β in Neonates

Neonatology ◽

10.1159/000507584 ◽

2020 ◽

pp. 1-10

Author(s):

Murwan Omer ◽

Ashanty Maggvie Melo ◽

Lynne Kelly ◽

Emma Jane Mac Dermott ◽

Timothy Ronan Leahy ◽

...

Keyword(s):

Cerebral Palsy ◽

Nlrp3 Inflammasome ◽

Therapeutic Target ◽

Inflammasome Activation ◽

Neonatal Brain ◽

Persistent Inflammation ◽

Attractive Therapeutic Target ◽

Clinical Models ◽

Novel Therapeutic

Infection and persistent inflammation have a prominent role in the pathogenesis of brain injury and cerebral palsy, as well as other conditions associated with prematurity such as bronchopulmonary dysplasia. The NLRP3 inflammasome-interleukin (IL)-1β pathway has been extensively studied in adults and pre-clinical models, improving our understanding of innate immunity and offering an attractive therapeutic target that is already contributing to clinical management in many auto-inflammatory disorders. IL-1 blockade has transformed the course and outcome of conditions such as chronic infantile neurological, cutaneous, articular (CINCA/NOMID) syndrome. Inflammasome activation and upregulation has recently been implicated in neonatal brain and lung inflammatory disease and may be a novel therapeutic target.

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Challenges in validating candidate therapeutic targets in cancer

eLife ◽

10.7554/elife.32402 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 12

Author(s):

Jeffrey Settleman ◽

Charles L Sawyers ◽

Tony Hunter

Keyword(s):

Cancer Research ◽

Protein Kinase ◽

Therapeutic Target ◽

Human Cancer ◽

Therapeutic Targets ◽

Compelling Evidence ◽

Attractive Therapeutic Target ◽

Research Tools

More than 30 published articles have suggested that a protein kinase called MELK is an attractive therapeutic target in human cancer, but three recent reports describe compelling evidence that it is not. These reports highlight the caveats associated with some of the research tools that are commonly used to validate candidate therapeutic targets in cancer research.

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Is Targeting the Inflammasome a Way Forward for Neuroscience Drug Discovery?

SLAS DISCOVERY Advancing Life Sciences ◽

10.1177/2472555218786210 ◽

2018 ◽

Vol 23 (10) ◽

pp. 991-1017 ◽

Cited By ~ 4

Author(s):

Tessa Swanton ◽

James Cook ◽

James A. Beswick ◽

Sally Freeman ◽

Catherine B. Lawrence ◽

...

Keyword(s):

Drug Discovery ◽

Drug Development ◽

Nlrp3 Inflammasome ◽

Therapeutic Target ◽

Neuronal Damage ◽

Critical Factor ◽

Inflammatory Signaling ◽

Potential Therapeutic Target ◽

Neurological Conditions ◽

The One

Neuroinflammation is becoming increasingly recognized as a critical factor in the pathology of both acute and chronic neurological conditions. Inflammasomes such as the one formed by NACHT, LRR, and PYD domains containing protein 3 (NLRP3) are key regulators of inflammation due to their ability to induce the processing and secretion of interleukin 1β (IL-1β). IL-1β has previously been identified as a potential therapeutic target in a variety of conditions due to its ability to promote neuronal damage under conditions of injury. Thus, inflammasome inhibition has the potential to curtail inflammatory signaling, which could prove beneficial in certain diseases. In this review, we discuss the evidence for inflammasome contributions to the pathology of neurodegenerative conditions such as Alzheimer’s disease and Parkinson’s disease, epilepsy, and acute degeneration following brain trauma or stroke. In addition, we review the current landscape of drug development targeting the NLRP3 inflammasome.

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Drug discovery in China: challenges and opportunities

National Science Review ◽

10.1093/nsr/nwy085 ◽

2018 ◽

Vol 5 (5) ◽

pp. 768-773

Author(s):

Ling Wang

Keyword(s):

Drug Discovery ◽

Drug Development ◽

Driving Forces ◽

Generic Drugs ◽

Innovation System ◽

Chinese Academy Of Sciences ◽

Challenges And Opportunities ◽

Peking University ◽

Academy Of Sciences ◽

Beijing China

Abstract Human history is also a chronicle of battling against diseases. Thanks to the rapid advancement of life science and biotechnologies such as gene editing and deep sequencing, recent decades have seen more and more untreatable illnesses on the verge of being conquered. However, an efficient drug-innovation system involves multiple driving forces—policy stimulation and commercial interests play important roles, besides advances in science and technology. Therefore, establishing the synergism among various driving forces is essential for new drug discovery and development. As the most populous country in the world, China has the largest population of a broad spectrum of diseases, offering a unique environment for research and development in biomedicine and disease therapies. Although most pharmaceutical companies in China have been focused on making generic drugs in the past, some efforts in developing first-in-class drugs are paying off, especially in the small-molecule drugs. What are the emerging trends in drug discovery? What does Artificial Intelligence (AI) bring to drug development and medical treatments? In the future, how will China take advantage of abundant resources and proactive policies to accelerate drug development? Recently, NSR organized a forum focusing on these issues, with the attendance of five distinguished domestic pharmaceutical scientists. Ke Ding Professor in the College of Pharmacy, Jinan University, Jinan, China Shengyong Yang Professor in the State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China Zhen Yang Professor in the Department of Chemistry, Peking University, Beijing, China Ao Zhang Professor in the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China Demin Zhou Professor in the School of Pharmaceutical Sciences, Peking University, Beijing, China Mu-ming Poo (Chair) Director of the Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Executive Editor-in-Chief of NSR, Shanghai, China

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Targeting MmpL3 for anti-tuberculosis drug development

Biochemical Society Transactions ◽

10.1042/bst20190950 ◽

2020 ◽

Vol 48 (4) ◽

pp. 1463-1472

Author(s):

Jani R. Bolla

Keyword(s):

Mycobacterium Tuberculosis ◽

Membrane Protein ◽

Drug Development ◽

Crystal Structures ◽

Therapeutic Target ◽

Cell Envelope ◽

Structural Features ◽

Lipid Transport ◽

Attractive Therapeutic Target ◽

Made In

The unique architecture of the mycobacterial cell envelope plays an important role in Mycobacterium tuberculosis (Mtb) pathogenesis. A critical protein in cell envelope biogenesis in mycobacteria, required for transport of precursors, trehalose monomycolates (TMMs), is the Mycobacterial membrane protein large 3 (MmpL3). Due to its central role in TMM transport, MmpL3 has been an attractive therapeutic target and a key target for several preclinical agents. In 2019, the first crystal structures of the MmpL3 transporter and its complexes with lipids and inhibitors were reported. These structures revealed several unique structural features of MmpL3 and provided invaluable information on the mechanism of TMM transport. This review aims to highlight the recent advances made in the function of MmpL3 and summarises structural findings. The overall goal is to provide a mechanistic perspective of MmpL3-mediated lipid transport and inhibition, and to highlight the prospects for potential antituberculosis therapies.

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