Synthesis of Rigidified eIF4E/eIF4G Inhibitor-1 (4EGI-1) Mimetic and Their in Vitro Characterization as Inhibitors of Protein–Protein Interaction

Poornachandran, M.; Takrouri, Khuloud; Chen, Ting; Sahoo, Rupam; Papadopoulos, Evangelos; Chen, Limo; Wagner, Gerhard; Aktas, Bertal H.; Halperin, José A.; Chorev, Michael

doi:10.1021/jm401733v

Cited by 23 publications

(21 citation statements)

References 52 publications

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“…The archetype of this family of compounds, 4EGI-1, suppressed the growth and induced apoptosis of multiple myeloma and lung cancer cells in vitro and inhibited myeloma and breast cancer xenografts without apparent toxicity in vivo [ 88 – 92 ]. Accordingly, current efforts are focused on developing more potent analogues of 4EGI [ 93 – 95 ]. Mechanistically, 4EGI-1 binds to a region of eIF4E that is distant from the eIF4E-eIF4G interface and induces an allosteric inhibition of the interaction between the two-subunits [ 87 ].…”

Section: Strategies For Targeting Eif4e In Cancer Therapymentioning

confidence: 99%

Signalling to eIF4E in cancer

Siddiqui

Sonenberg

2015

Biochemical Society Transactions

186

185

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Translational control plays a critical role in the regulation of gene expression in eukaryotes and affects many essential cellular processes, including proliferation, apoptosis and differentiation. Under most circumstances, translational control occurs at the initiation step at which the ribosome is recruited to the mRNA. The eukaryotic translation initiation factor 4E (eIF4E), as part of the eIF4F complex, interacts first with the mRNA and facilitates the recruitment of the 40S ribosomal subunit. The activity of eIF4E is regulated at many levels, most profoundly by two major signalling pathways: PI3K (phosphoinositide 3-kinase)/Akt (also known and Protein Kinase B, PKB)/mTOR (mechanistic/mammalian target of rapamycin) and Ras (rat sarcoma)/MAPK (mitogen-activated protein kinase)/Mnk (MAPK-interacting kinases). mTOR directly phosphorylates the 4E-BPs (eIF4E-binding proteins), which are inhibitors of eIF4E, to relieve translational suppression, whereas Mnk phosphorylates eIF4E to stimulate translation. Hyperactivation of these pathways occurs in the majority of cancers, which results in increased eIF4E activity. Thus, translational control via eIF4E acts as a convergence point for hyperactive signalling pathways to promote tumorigenesis. Consequently, recent works have aimed to target these pathways and ultimately the translational machinery for cancer therapy.

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Section: Strategies For Targeting Eif4e In Cancer Therapymentioning

confidence: 99%

Signalling to eIF4E in cancer

Siddiqui

Sonenberg

2015

Biochemical Society Transactions

186

185

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“…4EGI-1 has been used in studies examining the role of eIF4F complex in memory ( Hoeffer et al, 2011 ) and autism ( Gkogkas et al, 2013 ; Santini et al, 2013 ), where it was delivered directly to the brain (intracerebroventricular injection) as it does not readily penetrate the BBB. Rigidified analogs of 4EGI-1 have been developed, showing improved potency in inhibition of eIF4E/eIF4G interaction ( Mahalingam et al, 2014 ).…”

Section: Therapeutic Approaches To Target Eif4e-dependent Mechanisms mentioning

confidence: 99%

eIF4E-Dependent Translational Control: A Central Mechanism for Regulation of Pain Plasticity

et al. 2018

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Translational control of gene expression has emerged as a key mechanism in regulating different forms of long-lasting neuronal plasticity. Maladaptive plastic reorganization of peripheral and spinal nociceptive circuits underlies many chronic pain states and relies on new gene expression. Accordingly, downregulation of mRNA translation in primary afferents and spinal dorsal horn neurons inhibits tissue injury-induced sensitization of nociceptive pathways, supporting a central role for translation dysregulation in the development of persistent pain. Translation is primarily regulated at the initiation stage via the coordinated activity of translation initiation factors. The mRNA cap-binding protein, eukaryotic translation initiation factor 4E (eIF4E), is involved in the recruitment of the ribosome to the mRNA cap structure, playing a central role in the regulation of translation initiation. eIF4E integrates inputs from the mTOR and ERK signaling pathways, both of which are activated in numerous painful conditions to regulate the translation of a subset of mRNAs. Many of these mRNAs are involved in the control of cell growth, proliferation, and neuroplasticity. However, the full repertoire of eIF4E-dependent mRNAs in the nervous system and their translation regulatory mechanisms remain largely unknown. In this review, we summarize the current evidence for the role of eIF4E-dependent translational control in the sensitization of pain circuits and present pharmacological approaches to target these mechanisms. Understanding eIF4E-dependent translational control mechanisms and their roles in aberrant plasticity of nociceptive circuits might reveal novel therapeutic targets to treat persistent pain states.

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“…Rigidified variants of 4EGI-1 have been synthesized and characterized, with some capable of better inhibiting the eIF4E:eIF4G interaction than the parental compound ( Fig. 3C) (Mahalingam et al 2014). 4E1RCat and 4E2RCat prevent the association of both eIF4G and 4EBP1 with eIF4E ( Fig.…”

Section: Targeting the Eif4e:eif4g Interactionmentioning

confidence: 99%

Therapeutic Opportunities in Eukaryotic Translation

Chu

2018

Cold Spring Harb Perspect Biol

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The ability to block biological processes with selective small molecules provides advantages distinct from most other experimental approaches. These include rapid time to onset, swift reversibility, ability to probe activities in manners that cannot be accessed by genetic means, and the potential to be further developed as therapeutic agents. Small molecule inhibitors can also be used to alter expression and activity without affecting the stoichiometry of interacting partners. These tenets have been especially evident in the field of translation. Small molecule inhibitors were instrumental in enabling investigators to capture short-lived complexes and characterize specific steps of protein synthesis. In addition, several drugs that are the mainstay of modern antimicrobial drug therapy are potent inhibitors of prokaryotic translation. Currently, there is much interest in targeting eukaryotic translation as decades of research have revealed that deregulated protein synthesis in cancer cells represents a targetable vulnerability. In addition to being potential therapeutics, small molecules that manipulate translation have also been shown to influence cognitive processes such as memory. In this review, we focus on small molecule modulators that target the eukaryotic translation initiation apparatus and provide an update on their potential application to the treatment of disease.

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Synthesis of Rigidified eIF4E/eIF4G Inhibitor-1 (4EGI-1) Mimetic and Their in Vitro Characterization as Inhibitors of Protein–Protein Interaction

Cited by 23 publications

References 52 publications

Signalling to eIF4E in cancer

Signalling to eIF4E in cancer

eIF4E-Dependent Translational Control: A Central Mechanism for Regulation of Pain Plasticity

Therapeutic Opportunities in Eukaryotic Translation

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