2021
DOI: 10.1021/acsmedchemlett.0c00563
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Fragment-Based Discovery of Novel Allosteric MEK1 Binders

Abstract: The MEK1 kinase plays a critical role in key cellular processes, and as such, its dysfunction is strongly linked to several human diseases, particularly cancer. MEK1 has consequently received considerable attention as a drug target, and a significant number of small-molecule inhibitors of this kinase have been reported. The majority of these inhibitors target an allosteric pocket proximal to the ATP binding site which has proven to be highly druggable, with four allosteric MEK1 inhibitors approved to date. Des… Show more

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Cited by 9 publications
(16 citation statements)
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“…However, there are no table entries for papers targeting proteases, the first time this target class has not been represented. In contrast, there are more examples of GPCR case studies in Table than in previous years (entries 26, 27, and 28), including the description of the discovery of the M1 agonist clinical compound HTL9936 (entry 28). …”
Section: Resultsmentioning
confidence: 99%
See 1 more Smart Citation
“…However, there are no table entries for papers targeting proteases, the first time this target class has not been represented. In contrast, there are more examples of GPCR case studies in Table than in previous years (entries 26, 27, and 28), including the description of the discovery of the M1 agonist clinical compound HTL9936 (entry 28). …”
Section: Resultsmentioning
confidence: 99%
“…Notably, 4 of these examples are kinases (entries 1, 4, 9, and 10), a target class that has been extensively studied and is therefore well-suited to modeling. For example, Di Fruscia et al 10 described the identification of allosteric MEK binders (entry 1). The fragment screening used a number of methods (VS, NMR, SPR), focused on identifying allosteric binders.…”
Section: ■ Resultsmentioning
confidence: 99%
“…MEK1/2 inhibitors can inhibit both the ERK1/2 and ERK5 pathways+nd MEK2 have the ability to phosphorylate the T-E-Y motif in the kinase activation loop of ERK1/2, resulting in their activation. MEK1 dysfunction is strongly linked to cancer [18] .…”
Section: Discussionmentioning
confidence: 99%
“…Despite the importance of GSK-3β as a key target for several pathologies and the very high number of inhibitors that have been proposed over the years, the progression of these molecules to the clinical stage is extremely slow due to several challenges mainly related to off-target activity and toxicity [ 28 ]. To address these issues common to all protein kinases, the drug discovery research has been moved towards the search for allosteric inhibitors to identify molecules able to bind and inhibit the target with high selectivity [ 29 , 30 , 31 ]. The search for allosteric druggable pockets (other than the ATP binding site) for identifying highly selective GSK-3β inhibitors has been extensively carried out [ 32 , 33 , 34 , 35 ].…”
Section: Discussionmentioning
confidence: 99%