Insights into the binding mode of MEK type-III inhibitors. A step towards discovering and designing allosteric kinase inhibitors across the human kinome

Zhao, Zheng; Xie, Lei; Bourne, Philip E.

doi:10.1371/journal.pone.0179936

Cited by 40 publications

(32 citation statements)

References 47 publications

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“…S2-A), we hypothesized that 6-OH may be capable of directly inhibiting MEK1. To test this hypothesis, and gain insight into the plausibility of 6-OH acting as a small molecule kinase inhibitor, we conducted ligand-protein docking simulations using published crystal structures of MEK1 and 6-OH as well as a commercial inhibitor, PD0325901 (PD) (a type-III non-ATP competitive inhibitor, which are well studied (64,65)). Utilizing AutoDock Vina (66), which evaluated energetically optimized binding poses for each ligand, we found that both 6-OH and PD were placed around the well-characterized allosteric binding pocket for this type of inhibitor, without providing prior information on the binding surface.…”

Section: -Oh-bde-47 Is a Promiscuous Kinase Inhibitormentioning

confidence: 99%

Certain ortho-hydroxylated brominated ethers are promiscuous kinase inhibitors that impair neuronal signaling and neurodevelopmental processes

Poston

Rejepova

Ghaninejad-Esfahani

et al. 2020

Journal of Biological Chemistry

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The developing nervous system is remarkably sensitive to environmental signals, including disruptive toxins, such as polybrominated diphenyl ethers (PBDEs). PBDEs are an environmentally pervasive class of brominated flame retardants whose neurodevelopmental toxicity mechanisms remain largely unclear. Using dissociated cortical neurons from embryonic Rattus norvegicus, we found here that chronic exposure to 6-OH–BDE-47, one of the most prevalent hydroxylated PBDE metabolites, suppresses both spontaneous and evoked neuronal electrical activity. On the basis of our previous work on mitogen-activated protein kinase (MAPK)/extracellular signal-related kinase (ERK) (MEK) biology and our observation that 6-OH–BDE-47 is structurally similar to kinase inhibitors, we hypothesized that certain hydroxylated PBDEs mediate neurotoxicity, at least in part, by impairing the MEK–ERK axis of MAPK signal transduction. We tested this hypothesis on three experimental platforms: 1) in silico, where modeling ligand–protein docking suggested that 6-OH–BDE-47 is a promiscuous ATP-competitive kinase inhibitor; 2) in vitro in dissociated neurons, where 6-OH–BDE-47 and another specific hydroxylated BDE metabolite similarly impaired phosphorylation of MEK/ERK1/2 and activity-induced transcription of a neuronal immediate early gene; and 3) in vivo in Drosophila melanogaster, where developmental exposures to 6-OH–BDE-47 and a MAPK inhibitor resulted in offspring displaying similarly increased frequency of mushroom-body β–lobe midline crossing, a metric of axonal guidance. Taken together, our results support that certain ortho-hydroxylated PBDE metabolites are promiscuous kinase inhibitors and can cause disruptions of critical neurodevelopmental processes, including neuronal electrical activity, pre-synaptic functions, MEK–ERK signaling, and axonal guidance.

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Section: -Oh-bde-47 Is a Promiscuous Kinase Inhibitormentioning

confidence: 99%

Certain ortho-hydroxylated brominated ethers are promiscuous kinase inhibitors that impair neuronal signaling and neurodevelopmental processes

Poston

Rejepova

Ghaninejad-Esfahani

et al. 2020

Journal of Biological Chemistry

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“…Since the discovery of the first ERK experimental inhibitor PD98059 20 years ago [ 8 ], new MEK inhibitors occupying highly specific allosteric sites of the target molecules have provided the opportunity to achieve higher selectivity and have also contributed to validate MEK as a cancer drug target [ 9 ]. Two allosteric MEK inhibitors have received regulatory approval for the treatment of human cancers, namely trametinib and cobimetinib, in a protein kinase-specific drug discovery that continues today [ 10 ]. Finally, therapies that associate BRAF inhibitors with MEK inhibitors (dabrafenib with trametinib and vemurafenib with cobimetinib) are the current treatment strategies for BRAF -mutant advanced cancers, including melanoma [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

The MEK Inhibitors Trametinib and Cobimetinib Induce a Type I Interferon Response in Human Keratinocytes

Lulli

Carbone

Pastore

2017

IJMS

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Mitogen-activated protein kinase kinases (MEK) 1 and 2 have crucial roles in tumorigenesis, cell proliferation, and protection from apoptosis, and their inhibition is therefore an attractive therapeutic strategy in cancer. Orally available and highly selective MEK inhibitors have been developed and assessed in numerous clinical trials, either alone or in combination with cytotoxic chemotherapy and/or other targeted agents. Of note, a complex picture of class-specific adverse effects associates with these drugs, frequently including inflammatory skin rash. Here, we investigated the response of normal human keratinocytes to the MEK inhibitors trametinib and cobimetinib, alone and in combination with the v-Raf murine sarcoma viral oncogene homolog B (BRAF) inhibitors dabrafenib and vemurafenib, in terms of signal transduction and de novo gene expression. MEK inhibitors triggered enhanced expression of interferon regulatory factor 1 (IRF1) and phosphorylation of signal transducer and activator of transcription 1 (STAT1), and up-regulated the keratinocyte-specific type I interferon κ (IFN-κ), the anti-viral effectors interferon-induced tetratricopeptide repeats (IFIT) 1 and 2, and the pro-inflammatory chemokine (C-C motif) ligand 2 (CCL2) and the C-X-C motif chemokine 10 (CXCL10), both at the mRNA and protein level. Impairment of IRF1 expression, or abrogation of STAT1 phosphorylation due to IFN-κ gene silencing, suppressed anti-viral and pro-inflammatory gene expression. These data suggest that, similar to what we observed for epidermal growth factor receptor (EGFR) blockade, MEK inhibition activates a type I interferon response, which is now recognized as an effective anti-cancer response, in human epidermal keratinocytes.

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“…The unique structural features adjacent to the ATP-binding site of MEK1/2 have been used to identify compounds that inhibit MEK1/2 activity and may have applications targeting other kinases. Zhao et al have presented an excellent review of the type III kinase inhibitor-binding mode with a focus on interactions with MEK1/2 proteins [ 11 ]. These studies provide evidence that unique structural features in catalytic/kinase domains can be exploited to design more selective kinase inhibitors.…”

Section: Part A: Type III Kinase Inhibitorsmentioning

confidence: 99%

“…The activation loop of the MEK1/2 proteins is unique in that it forms a short helix that allows specific interactions with type III inhibitors [ 4 ]. While the activation loop is typically disordered in kinases where structural information is available, other kinases including p38α MAP kinase and B-Raf kinase, along with MEK1/2, have been reported to adopt these short helix structures in the activation loop [ 11 ]. Thus, this unique structural feature could be used to develop type III inhibitors for other kinases.…”

Section: Part A: Type III Kinase Inhibitorsmentioning

confidence: 99%

See 1 more Smart Citation

Avoiding or Co-Opting ATP Inhibition: Overview of Type III, IV, V, and VI Kinase Inhibitors

Martínez

Defnet

Shapiro

2020

Next Generation Kinase Inhibitors

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As described in the previous chapter, most kinase inhibitors that have been developed for use in the clinic act by blocking ATP binding; however, there is growing interest in identifying compounds that target kinase activities and functions without interfering with the conserved features of the ATP-binding site. This chapter will highlight alternative approaches that exploit unique kinase structural features that are being targeted to identify more selective and potent inhibitors. The figure below, adapted from (Sammons et al., Molecular Carcinogenesis 58:1551–1570, 2019), provides a graphical description of the various approaches to manipulate kinase activity. In addition to the type I and II inhibitors, type III kinase inhibitors have been identified to target sites adjacent to the ATP-binding site in the catalytic domain. New information on kinase structure and substrate-binding sites has enabled the identification of type IV kinase inhibitor compounds that target regions outside the catalytic domain. The combination of targeting unique allosteric sites outside the catalytic domain with ATP-targeted compounds has yielded a number of novel bivalent type V kinase inhibitors. Finally, emerging interest in the development of irreversible compounds that form selective covalent interactions with key amino acids involved in kinase functions comprise the class of type VI kinase inhibitors.

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Insights into the binding mode of MEK type-III inhibitors. A step towards discovering and designing allosteric kinase inhibitors across the human kinome

Cited by 40 publications

References 47 publications

Certain ortho-hydroxylated brominated ethers are promiscuous kinase inhibitors that impair neuronal signaling and neurodevelopmental processes

Certain ortho-hydroxylated brominated ethers are promiscuous kinase inhibitors that impair neuronal signaling and neurodevelopmental processes

The MEK Inhibitors Trametinib and Cobimetinib Induce a Type I Interferon Response in Human Keratinocytes

Avoiding or Co-Opting ATP Inhibition: Overview of Type III, IV, V, and VI Kinase Inhibitors

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