Impact of Allosteric Modulation in Drug Discovery: Innovation in Emerging Chemical Modalities

Han, Bingsong; Salituro, Francesco G.; Blanco, Marı́a-Jesús

doi:10.1021/acsmedchemlett.9b00655

Cited by 42 publications

(32 citation statements)

References 56 publications

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“…Classically, type III inhibitors displace the c-helix and prevent MEK activation via dual phosphorylation on the TEY motif. There has, however, been an increasing awareness [36][37][38][39][40][41] that type-III kinase binders may induce additional allosteric modification beyond displacement of the C-helix. There also exists the possibility that SC-1-151 may have interactions at other MEK5 allosteric sites, may modify a MEK5 protein/protein interaction, or have activity at a yet uncharacterized protein.…”

Section: Discussionmentioning

confidence: 99%

Constitutive activation of MEK5 promotes a mesenchymal and migratory cell phenotype in triple negative breast cancer

et al. 2021

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Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited targeted therapeutic options. A defining feature of TNBC is the propensity to metastasize and acquire resistance to cytotoxic agents. Mitogen activated protein kinase (MAPK) and extracellular regulated kinase (ERK) signaling pathways have integral roles in cancer development and progression. While MEK5/ ERK5 signaling drives mesenchymal and migratory cell phenotypes in breast cancer, the specific mechanisms underlying these actions remain under-characterized. To elucidate the mechanisms through which MEK5 regulates the mesenchymal and migratory phenotype, we generated stably transfected constitutively active MEK5 (MEK5-ca) TNBC cells. Downstream signaling pathways and candidate targets of MEK5-ca cells were based on RNA sequencing and confirmed using qPCR and Western blot analyses. MEK5 activation drove a mesenchymal cell phenotype independent of cell proliferation effects. Transwell migration assays demonstrated MEK5 activation significantly increased breast cancer cell migration. In this study,we provide supporting evidence that MEK5 functions through FRA-1 to regulate the mesenchymal and migratory phenotype in TNBC.

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Section: Discussionmentioning

confidence: 99%

Constitutive activation of MEK5 promotes a mesenchymal and migratory cell phenotype in triple negative breast cancer

et al. 2021

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“…Another interesting chemical modality that is currently receiving much attention is the design and synthesis of allosteric modulators [61][62][63]. This modality offers significant advantages over the development of orthosteric agonists, enabling much more fine-tuned modulation of the receptor only in the presence of the endogenous ligand.…”

Section: Application Of Cross-coupling Reactions To Allosteric Modulamentioning

confidence: 99%

Impact of Cross-Coupling Reactions in Drug Discovery and Development

2020

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Cross-coupling reactions have played a critical role enabling the rapid expansion of structure–activity relationships (SAR) during the drug discovery phase to identify a clinical candidate and facilitate subsequent drug development processes. The reliability and flexibility of this methodology have attracted great interest in the pharmaceutical industry, becoming one of the most used approaches from Lead Generation to Lead Optimization. In this mini-review, we present an overview of cross-coupling reaction applications to medicinal chemistry efforts, in particular the Suzuki–Miyaura and Buchwald–Hartwig cross-coupling reactions as a remarkable resource for the generation of carbon–carbon and carbon–heteroatom bonds. To further appreciate the impact of this methodology, the authors discuss some recent examples of clinical candidates that utilize key cross-coupling reactions in their large-scale synthetic process. Looking into future opportunities, the authors highlight the versatility of the cross-coupling reactions towards new chemical modalities like DNA-encoded libraries (DELs), new generation of peptides and cyclopeptides, allosteric modulators, and proteolysis targeting chimera (PROTAC) approaches.

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“…By evaluating the ERK1/2 phosphorylation upon the treatment with the “antagonists” in the calcium assay, we identified compound 1 m as a putative β‐arrestin‐biased allosteric superagonist. Although allosteric binding sites are said to be less preserved compared with the orthosteric ones, [25] some studies predict the existence of conserved allosteric binding pocket in GPCRs [26] . A β‐arrestin‐biased allosteric agonist has been identified for neurotensin receptor 1 (NTSR1), [27] a GPCR closely related to GHSR [28] .…”

Section: Discussionmentioning

confidence: 99%

Identification of a Putative β‐Arrestin Superagonist of the Growth Hormone Secretagogue Receptor (GHSR)

et al. 2021

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Ghrelin is a pleiotropic feeding hormone which also has a pivotal role in the central nervous system. Upon the activation of its receptor, growth hormone secretagogue receptor (GHSR), the Gαq/11‐mediated and the β‐arrestin‐mediated signaling pathways are activated. As the β‐arrestin pathway is a potential drug target, there is a strong need for β‐arrestin‐biased GHSR modulators. Activation of the β‐arrestin pathway should inhibit the Gαq/11‐mediated calcium flux through internalization of the receptor. Hence, we used the antagonistic activity in the calcium assay as the first screening for the β‐arrestin activation. By conducting the second screening assay for the β‐arrestin activation based on extracellular signal regulated kinase (ERK) 1/2 phosphorylation, we discovered a putative β‐arrestin‐biased superagonist. The activity of the compound was not completely blocked with the competitive antagonist, which implies that the effect is mediated, at least partly, by allosteric binding of the compound.

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Impact of Allosteric Modulation in Drug Discovery: Innovation in Emerging Chemical Modalities

Cited by 42 publications

References 56 publications

Constitutive activation of MEK5 promotes a mesenchymal and migratory cell phenotype in triple negative breast cancer

Constitutive activation of MEK5 promotes a mesenchymal and migratory cell phenotype in triple negative breast cancer

Impact of Cross-Coupling Reactions in Drug Discovery and Development

Identification of a Putative β‐Arrestin Superagonist of the Growth Hormone Secretagogue Receptor (GHSR)

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