Small molecule ERK5 kinase inhibitors paradoxically activate ERK5 signalling: be careful what you wish for…

Cook, Simon J.; Tucker, J.A.; Lochhead, Pamela A.

doi:10.1042/bst20190338

Cited by 24 publications

(31 citation statements)

References 94 publications

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“…One issue emerging from those data, as well as from the discovery of a potentially kinase-independent transcriptional function of ERK5, is whether tumor-suppressive strategies should merely target the kinase activity or additionally aim to suppress the ERK5 transcriptional capacity. Besides XMD8-92, several other small molecule inhibitors for ERK5 have been developed (reviewed in [ 128 ]). Surprisingly, recent data with novel highly specific ERK5 kinase inhibitors suggest that efficient ERK5 kinase inhibition may induce paradoxical transcriptional activation of ERK5 [ 129 ].…”

Section: Erk5 In Mechanical Stress-exposed Tissues and Mapk Inhibitor-resistant Cancersmentioning

confidence: 99%

The MEK5/ERK5 Pathway in Health and Disease

Paudel

Fusi

Schmidt

2021

IJMS

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The MEK5/ERK5 mitogen-activated protein kinases (MAPK) cascade is a unique signaling module activated by both mitogens and stress stimuli, including cytokines, fluid shear stress, high osmolarity, and oxidative stress. Physiologically, it is mainly known as a mechanoreceptive pathway in the endothelium, where it transduces the various vasoprotective effects of laminar blood flow. However, it also maintains integrity in other tissues exposed to mechanical stress, including bone, cartilage, and muscle, where it exerts a key function as a survival and differentiation pathway. Beyond its diverse physiological roles, the MEK5/ERK5 pathway has also been implicated in various diseases, including cancer, where it has recently emerged as a major escape route, sustaining tumor cell survival and proliferation under drug stress. In addition, MEK5/ERK5 dysfunction may foster cardiovascular diseases such as atherosclerosis. Here, we highlight the importance of the MEK5/ERK5 pathway in health and disease, focusing on its role as a protective cascade in mechanical stress-exposed healthy tissues and its function as a therapy resistance pathway in cancers. We discuss the perspective of targeting this cascade for cancer treatment and weigh its chances and potential risks when considering its emerging role as a protective stress response pathway.

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Section: Erk5 In Mechanical Stress-exposed Tissues and Mapk Inhibitor-resistant Cancersmentioning

confidence: 99%

The MEK5/ERK5 Pathway in Health and Disease

Paudel

Fusi

Schmidt

2021

IJMS

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“…Of particular interest amongst the putative hits identified within this screen was ERK5 (also known as MAPK7 and MEK5), as it has recently been identified as a potential oncogenic factor in several other cancers [ 6 , 7 , 8 , 9 , 10 , 11 , 18 , 19 , 20 ], and several potential therapeutic small molecule inhibitors have recently been developed [ 12 , 13 , 14 , 15 , 21 ]. To further validate ERK5 as promoting TMZ resistance in glioma cells and to discount potential off-target RNAi effects, we used siPOOLs consisting of 30 individual low nM siRNA that have been shown to give effective knockdown at low total nM concentrations ( Figure S1B ) with reduced off-target effects [ 22 ].…”

Section: Resultsmentioning

confidence: 99%

Identification and Validation of ERK5 as a DNA Damage Modulating Drug Target in Glioblastoma

Carmell

Rominiyi

Myers

et al. 2021

Cancers

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Brain tumours kill more children and adults under 40 than any other cancer, with approximately half of primary brain tumours being diagnosed as high-grade malignancies known as glioblastomas. Despite de-bulking surgery combined with chemo-/radiotherapy regimens, the mean survival for these patients is only around 15 months, with less than 10% surviving over 5 years. This dismal prognosis highlights the urgent need to develop novel agents to improve the treatment of these tumours. To address this need, we carried out a human kinome siRNA screen to identify potential drug targets that augment the effectiveness of temozolomide (TMZ)—the standard-of-care chemotherapeutic agent used to treat glioblastoma. From this we identified ERK5/MAPK7, which we subsequently validated using a range of siRNA and small molecule inhibitors within a panel of glioma cells. Mechanistically, we find that ERK5 promotes efficient repair of TMZ-induced DNA lesions to confer cell survival and clonogenic capacity. Finally, using several glioblastoma patient cohorts we provide target validation data for ERK5 as a novel drug target, revealing that heightened ERK5 expression at both the mRNA and protein level is associated with increased tumour grade and poorer patient survival. Collectively, these findings provide a foundation to develop clinically effective ERK5 targeting strategies in glioblastomas and establish much-needed enhancement of the therapeutic repertoire used to treat this currently incurable disease.

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“…Remarkably, in most of these cases, ATP-competitive binding of the inhibitors induce conformational changes, which activate noncatalytic functions of these kinases. 37 , 68 …”

Section: Discussionmentioning

confidence: 99%

“… 29 Studies on inhibitors of other protein kinases have however revealed that some Type I kinase inhibitors are prone to activate noncatalytic functions of the target protein. 35 − 37 For the clinical translation of the mainly genetic-based proposal of targeting MNKs as a promising new strategy in oncology, it is therefore desirable to identify non-ATP-competitive inhibitors to evaluate different modes of kinase inhibition in preclinical and clinical settings.…”

Section: Introductionmentioning

confidence: 99%

Overcoming Paradoxical Kinase Priming by a Novel MNK1 Inhibitor

et al. 2022

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Targeting the kinases MNK1 and MNK2 has emerged as a valuable strategy in oncology. However, most of the advanced inhibitors are acting in an adenosine triphosphate (ATP)-competitive mode, precluding the evaluation of different binding modes in preclinical settings. Using rational design, we identified and validated the 4,6-diaryl-pyrazolo[3,4- b ]pyridin-3-amine scaffold as the core for MNK inhibitors. Signaling pathway analysis confirmed a direct effect of the hit compound EB1 on MNKs, and in line with the reported function of these kinases, EB1 only affects the growth of tumor but not normal cells. Molecular modeling revealed the binding of EB1 to the inactive conformation of MNK1 and the interaction with the specific DFD motif. This novel mode of action appears to be superior to the ATP-competitive inhibitors, which render the protein in a pseudo-active state. Overcoming this paradoxical activation of MNKs by EB1 represents therefore a promising starting point for the development of a novel generation of MNK inhibitors.

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Small molecule ERK5 kinase inhibitors paradoxically activate ERK5 signalling: be careful what you wish for…

Cited by 24 publications

References 94 publications

The MEK5/ERK5 Pathway in Health and Disease

The MEK5/ERK5 Pathway in Health and Disease

Identification and Validation of ERK5 as a DNA Damage Modulating Drug Target in Glioblastoma

Overcoming Paradoxical Kinase Priming by a Novel MNK1 Inhibitor

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