Fragment-Based Discovery of Novel Allosteric MEK1 Binders

Fruscia, Paolo Di; Edfeldt, Fredrik; Shamovsky, Igor L.; Collie, Gavin W.; Aagaard, Anna; Barlind, Louise; Börjesson, Ulf; Hansson, Erik; Lewis, Richard J.; Nilsson, Magnus; Öster, Linda; Pemberton, Josefine; Ripa, Lena; Storer, Richard; Käck, Helena

doi:10.1021/acsmedchemlett.0c00563

Cited by 10 publications

(16 citation statements)

References 28 publications

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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%

“…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%

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Fragment-to-Lead Medicinal Chemistry Publications in 2021

Walsh¹,

Erlanson²,

Esch

et al. 2023

J. Med. Chem.

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This Perspective is the seventh in an annual series that summarizes successful Fragment-to-Lead (F2L) case studies published in a given year. A tabulated summary of relevant articles published in 2021 is provided, and features such as target class, screening methods, and ligand efficiency are discussed, both for the 2021 examples and for the combined examples over the years 2015−2021. In addition, trends and new developments in the field are summarized. In particular, the use of structural information in fragment-based drug discovery is discussed.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Resultsmentioning

confidence: 99%

Fragment-to-Lead Medicinal Chemistry Publications in 2021

Walsh¹,

Erlanson²,

Esch

et al. 2023

J. Med. Chem.

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“…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%

Three-Pronged Approach to Curb Cancer Metastasis

Kalsoom

Naeem

2023

J. Univ. Med. Dent. Coll.

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BACKGROUND & OBJECTIVE: Extracellular signal-regulated kinases 1 and 2 [ERK1/2] have been reported to promote cancer spread through receptor tyrosine kinase (RTK)/Ras/Raf/MEK/ERK1/2 pathway hyperactivation. The extracellular signal-regulated kinase ERK5 has also been linked to cancer. However, inhibition of ERK1/2 has been reported to cause compensatory hyperactivation of the ERK5 pathway. Therefore, there is a need for simultaneous inhibition of this trio by a common inhibitor. This study aimed to find a novel common inhibitor for ERK1, ERK2 and ERK5, with a special focus on phytochemicals. METHODOLOGY: All the available co-crystallized inhibitors of MEK1, ERK1/2 and ERK5 were used as references for 2D search across zillions of compounds. One hundred molecules with the best matching pharmacophores were extracted per virtual chemical space. A total of 20,000 new structurally diverse chemical entities with scaffold hopping ability were sifted out from these chemical spaces. Virtual screening of ERK1/2 and ERK5 was performed against these compounds. The successfully docked molecules with estimated affinities less than 500 nm were filtered. These filtered protein-molecule complexes of ERK1/2 and ERK5 were exported as Excel sheets, which were then compared to find any overlapping inhibitors. Four novel common/overlapping potential inhibitors were identified. Their pose views were generated, and binding interactions were analyzed. These novel compounds were compared for their absorption, distribution, metabolism, excretion and toxicity (ADME-Tox) properties. RESULTS: The molecules m240690bcc215667167368734, rxn109fEMOL37110279EMOL314046334 and LIND027BT1904LN00213276AK0086 showed good binding affinities to the conventional ATP binding pockets of the kinases ERK1/2 and ERK5. CONCLUSION: These novel compounds may be proposed as potential common inhibitors of ERK1, 2 and 5. Further in silico analysis and in vitro testing of proteins are required to confirm their inhibitory potential.

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“…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%

Identification of Novel GSK-3β Hits Using Competitive Biophysical Assays

Balboni

Tripathi

Veronesi

et al. 2022

IJMS

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Glycogen synthase kinase 3 beta (GSK-3β) is an evolutionarily conserved serine-threonine kinase dysregulated in numerous pathologies, such as Alzheimer’s disease and cancer. Even though GSK-3β is a validated pharmacological target most of its inhibitors have two main limitations: the lack of selectivity due to the high homology that characterizes the ATP binding site of most kinases, and the toxicity that emerges from GSK-3β complete inhibition which translates into the impairment of the plethora of pathways GSK-3β is involved in. Starting from a 1D 19F NMR fragment screening, we set up several biophysical assays for the identification of GSK-3β inhibitors capable of binding protein hotspots other than the ATP binding pocket or to the ATP binding pocket, but with an affinity able of competing with a reference binder. A phosphorylation activity assay on a panel of several kinases provided selectivity data that were further rationalized and corroborated by structural information on GSK-3β in complex with the hit compounds. In this study, we identified promising fragments, inhibitors of GSK-3β, while proposing an alternative screening workflow that allows facing the flaws that characterize the most common GSK-3β inhibitors through the identification of selective inhibitors and/or inhibitors able to modulate GSK-3β activity without leading to its complete inhibition.

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Fragment-Based Discovery of Novel Allosteric MEK1 Binders

Cited by 10 publications

References 28 publications

Fragment-to-Lead Medicinal Chemistry Publications in 2021

Fragment-to-Lead Medicinal Chemistry Publications in 2021

Three-Pronged Approach to Curb Cancer Metastasis

Identification of Novel GSK-3β Hits Using Competitive Biophysical Assays

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