Article
Chemistry, Medicinal
Weijun Xu, Srinivasaraghavan Kannan, Chandra S. Verma, Kassoum Nacro
Summary: MNK1/2 are central enzymes activated by ERK or p38 MAP kinases, coordinating cellular signaling and regulating cell proliferation and survival. Overexpression of MNK1/2 and/or eIF4E is associated with diseases including cancer, neurological disorders, autism, and inflammation. There are ongoing efforts to develop potent and selective inhibitors of MNK1/2 in both academia and industry.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Chemistry, Medicinal
Xin Jin, Rilei Yu, Xuemin Wang, Christopher G. Proud, Tao Jiang
Summary: MNKs phosphorylate eIF4E, playing a crucial role in cancer and metabolic diseases. Inhibitors of MNKs can be used for the treatment of various cancers, including solid tumors and leukemia.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Biotechnology & Applied Microbiology
Candice Mazewski, Leonidas C. Platanias
Summary: In leukemia, resistance to therapy is a major concern for survival. MAPK-interacting kinases (MNKs) have emerged as important activators of oncogenic-related signaling and potential mediators of resistance. Recent studies have shown promising preclinical efficacy of MNK inhibitors in combination formats or for treating chemotherapy-resistant cells, suggesting potential for use in clinical trials.
ONCOTARGETS AND THERAPY
(2023)
Review
Chemistry, Medicinal
Shuo Li, Jia-shu Chen, Xiangqian Li, Xiaoyi Bai, Dayong Shi
Summary: Overexpression of eIF4E is common in various solid tumors and hematologic cancers, making it a potential anti-cancer target. This review provides a detailed classification and description of the anti-cancer activities of promising compounds, concluding that MNK1/2 and eIF4E/eIF4G interaction inhibitors are superior to mTOR inhibitors for targeted therapy.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Patrick Senechal, Francis Robert, Regina Cencic, Akiko Yanagiya, Jennifer Chu, Nahum Sonenberg, Marilene Paquet, Jerry Pelletier
Summary: The translation initiation factor eIF4F is crucial for cap-dependent protein synthesis initiation. Different subunits of eIF4F have varying roles in development and tumorigenesis, with some being essential for viability and tumor onset, while others have non-essential functions. This study highlights the complex roles of different eIF4F subunits in gene expression regulation during embryogenesis and tumor development.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2021)
Article
Pharmacology & Pharmacy
Yuanyuan Zhu, Changying Wang, Mingqun Li, Xiaoyu Yang
Summary: This study demonstrated that Cercosporamide could effectively overcome chemoresistance in cervical cancer by targeting eIF4E via MNK inhibition. The drug showed preferential inhibition on cancer cells compared to normal cells, leading to enhanced efficacy of doxorubicin and cisplatin both in vitro and in vivo.
JOURNAL OF PHARMACY AND PHARMACOLOGY
(2021)
Article
Cell Biology
Dorota Gil, Marta Zarzycka, Joanna Pabijan, Ma lgorzata Lekka, Joanna Duli Dulinska-Litewka
Summary: Melanoma is resistant to chemotherapy and lacks fully effective targeted therapies. The mutations in melanoma lead to the hyperactivation of the MAPK and PI3K/AKT/mTOR pathways, which are responsible for abnormal protein synthesis. In this study, we investigated the effects of a specific PI3K/mTOR inhibitor, dactolisib, and Mnk inhibitor -CGP57380, alone and in combination on human melanoma cell lines. Both drugs showed inhibition of cell proliferation and migration when used individually, but their combination had additional antitumor effects. Simultaneous inhibition of both pathways may help overcome drug resistance.
CELLULAR SIGNALLING
(2023)
Article
Biochemistry & Molecular Biology
Benjamin Weiss, Pascale Jaquier-Gubler, Joseph Alphonsus Curran
Summary: This study focuses on a series of cellular molecular processes during translation initiation, including recruitment of small ribosome, recognition of mRNA, and the impact of eIF4E-5' cap interaction in the context of different TL lengths. The findings reveal the significance of these molecular interactions in protein synthesis and provide insights into the current recruitment models.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Medicinal
Xin Jin, Tingting Qiu, Jianling Xie, Xianfeng Wei, Xuemin Wang, Rilei Yu, Christopher Proud, Tao Jiang
Summary: A series of novel MNK inhibitors were reported in this study, among which compound 18 showed potent inhibition of eIF4E phosphorylation in various cancer cell lines. Compound 18 selectively targeted MNK2, decreased the levels of key proteins, arrested the cell cycle, inhibited cell migration, and suppressed the secretion of cytokines. It represents a starting compound for further design of selective MNK inhibitors and their applications in other diseases.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Chemistry, Medicinal
Xin Jin, Maowei Li, Tingting Qiu, Rilei Yu, Tao Jiang
Summary: In this study, hit compounds targeting MNK1 and MNK2 were identified using the MarineChem3D database. The compounds from the phorbazole family showed good interaction with MNK1. Further analysis led to the design and synthesis of 29 derivatives, of which six compounds exhibited good inhibition against MNKs. The study also confirmed the vital interactions between these compounds and MNK1, providing important information for developing MNK inhibitors based on this structural class.
Article
Pharmacology & Pharmacy
Jie Yang, Gang Li, Yue'e Huang, Ying Liu
Summary: PHB2 is a key signalling protein involved in a variety of cellular functions, and its overexpression is frequently observed in cancer, including renal cell carcinoma (RCC), where it is associated with poor overall survival rate. In this study, high levels of PHB2 were found in RCC tissues, and its downregulation displayed tumor-inhibiting effects in vitro, including proliferation retardation, cell cycle arrest, suppression of metastasis, and enhancement of chemosensitivity. Mechanistically, PHB2 mediated the activation of eIF4E and the translation of oncogenic proteins via the regulation of MNK. Furthermore, decreasing PHB2 in RCC cells weakened their ability to form xenografts in vivo. These findings suggest that targeting the PHB2/MNK/eIF4E pathway may hold therapeutic potential for RCC.
TOXICOLOGY AND APPLIED PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Xueju Qi, Shuna Zhang, Zekun Chen, Lijun Wang, Wenyong Zhu, Chuanjin Yin, Junting Fan, Xiaochen Wu, Jing Wang, Chuanlong Guo
Summary: eIF4E plays a key role in regulating tumor growth and angiogenesis in lung cancer. Compound EGPI-1 inhibits the proliferation of lung cancer cells without affecting normal cells. It interferes with the eIF4E/eIF4G interaction and inhibits the Ras/MNK/ERK/eIF4E signaling pathway. Moreover, it exhibits anti-angiogenic activity. EGPI-1 shows promise as a novel anti-lung cancer drug.
CHEMICO-BIOLOGICAL INTERACTIONS
(2022)
Article
Chemistry, Medicinal
Patrick D. Fischer, Evangelos Papadopoulos, Jon M. Dempersmier, Zi-Fu Wang, Radoslaw P. Nowak, Katherine A. Donovan, Joann Kalabathula, Christoph Gorgulla, Pierre P. M. Junghanns, Eihab Kabha, Nikolaos Dimitrakakis, Ognyan Petrov, Constantine Mitsiades, Christian Ducho, Vladimir Gelev, Eric S. Fischer, Gerhard Wagner, Haribabu Arthanari
Summary: The translation initiation factor eIF4E is a key regulator of cap-dependent protein synthesis, with overexpression implicated in diseases like cancer. A novel inhibitor, i4EG-BiP, has been shown to displace eIF4G and inhibit cancer cell proliferation. Efforts to design PROTACs targeting eIF4E for proteasomal degradation have faced challenges, such as competitive effects from 4E-BP1 binding.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Neurosciences
Dong Liu, Jin Li, Hao Lin, Ethan Lorsung, Nam Le, Rubal Singla, Abhishek Mishra, Rikiro Fukunaga, Ruifeng Cao
Summary: This study investigates the distribution and temporal regulation of eIF4E phosphorylation in the brain and its role in regulating diurnal oscillations of cognitive functions. The findings suggest that the circadian activities of the MNK-eIF4E axis contribute to the diurnal rhythms of cognitive functions, highlighting the importance of rhythmic translational control in circadian regulation of cognitive performance.
EUROPEAN JOURNAL OF NEUROSCIENCE
(2022)
Article
Pharmacology & Pharmacy
Qi Zhang, Hui Li, Quan Li, Qiyan Hu, Bo Liu
Summary: This study reveals for the first time that eIF4E expression and activity are upregulated in anlotinib-resistant NSCLC cells, and depletion of eIF4E significantly inhibits proliferation and induces apoptosis in resistant cells. Additionally, we found that cercosporamide, an MNK-dependent eIF4E inhibitor, can overcome anlotinib resistance and enhance its efficacy in non-resistant NSCLC cells. The importance of these findings is further supported by consistent results from in vivo and in vitro experiments.
FUNDAMENTAL & CLINICAL PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Jianling Xie, Kaikai Shen, Ashley T. Jones, Jian Yang, Andrew R. Tee, Ming Hong Shen, Mengyuan Yu, Swati Irani, Derick Wong, James E. Merrett, Roman Lenchine, Stuart De Poi, Kirk B. Jensen, Paul J. Trim, Marten F. Snel, Makoto Kamei, Sally Kim Martin, Stephen Fitter, Shuye Tian, Xuemin Wang, Lisa M. Butler, Andrew C. W. Zannettino, Christopher G. Proud
Summary: This study uncovers a novel feedback loop in which mTORC1 represses MNK2 activity and oncogenic signaling through eIF4E phosphorylation, providing insights into the reciprocal regulation of these two oncogenic pathways.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Thomas D. Burton, Anthony O. Fedele, Jianling Xie, Lauren Y. Sandeman, Christopher G. Proud
JOURNAL OF BIOLOGICAL CHEMISTRY
(2020)
Article
Biochemistry & Molecular Biology
Luis F. H. Gladulich, Jianling Xie, Kirk B. Jensen, Makoto Kamei, Roberto Paes-de-Carvalho, Marcelo Cossenza, Christopher G. Proud
Summary: This study investigated the localization control of eEF2K and its impact on protein synthesis in neuronal cells. Modifying eEF2K function through pharmacological and/or genetic approaches revealed that eEF2K activity and localization can be regulated by its binding partner Homer1b/c and the mTORC1 signaling pathway.
JOURNAL OF NEUROCHEMISTRY
(2021)
Article
Genetics & Heredity
Inna Slynko, Stephanie Nguyen, Eline M. C. Hamilton, Lisanne E. Wisse, Iwan J. P. de Esch, Chris de Graaf, John B. Bruning, Christopher G. Proud, Truus E. M. Abbink, Marjo S. van der Knaap
Summary: This study analyzed 97 missense mutations in vanishing white matter disease (VWM) and found that over 50% of mutations have (ultra-)severe phenotypic effects. Approximately 60% of mutations affect the ε-subunit containing the catalytic domain, while about 36% affect subunit interfaces, mostly with severe effects.
MOLECULAR GENETICS & GENOMIC MEDICINE
(2021)
Article
Biotechnology & Applied Microbiology
Stuart P. De Poi, Jianling Xie, C. Mark Smales, Christopher G. Proud
Summary: The study demonstrates that expressing certain constitutively active mutants of Rheb in CHO cells can lead to faster protein synthesis and increased secretion of valuable proteins, providing a simple approach to promoting cell growth and production of high commercial value secreted proteins in defined media.
BIOTECHNOLOGY AND BIOENGINEERING
(2021)
Article
Biochemistry & Molecular Biology
Roman Lenchine, Sushma R. Rao, Xuemin Wang, Danielle Meiwen Fang, Christopher G. Proud
Summary: Cells in solid tumors can survive under nutrient deprivation by utilizing autophagy and eEF2K mechanisms, regulated by AMP-activated protein kinase and mechanistic target of rapamycin complex 1 signaling pathways. Disrupting both autophagy and eEF2K compromises the survival of lung and breast cancer cells, highlighting the importance of these processes in cancer cell survival.
BIOCHEMICAL JOURNAL
(2021)
Article
Biochemistry & Molecular Biology
Jianling Xie, Stuart P. De Poi, Sean J. Humphrey, Leanne K. Hein, John B. Bruning, Wenru Pan, Luke A. Selth, Timothy J. Sargeant, Christopher G. Proud
Summary: The study demonstrates that various recurrent Rheb mutations drive hyperactive mTORC1 signaling through different levels of insensitivity to the main inhibitor of Rheb, tuberous sclerosis complex. Among them, two activated mutants, Rheb-T23M and E40K, significantly promote cell growth, proliferation, and anchorage-independent growth, leading to enhanced tumor growth in vivo. Proteomic analysis reveals that these mutants activate distinct oncogenic pathways, with Rheb-T23M enhancing anaerobic glycolysis and Rheb-E40K regulating eEF2 and autophagy, possibly through interactions with AMPK.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2021)
Article
Cell Biology
Miriam A. Lynn, Georgina Eden, Feargal J. Ryan, Julien Bensalem, Xuemin Wang, Stephen J. Blake, Jocelyn M. Choo, Yee Tee Chern, Anastasia Sribnaia, Jane James, Saoirse C. Benson, Lauren Sandeman, Jianling Xie, Sofia Hassiotis, Emily W. Sun, Alyce M. Martin, Marianne D. Keller, Damien J. Keating, Timothy J. Sargeant, Christopher G. Proud, Steve L. Wesselingh, Geraint B. Rogers, David J. Lynn
Summary: After antibiotic exposure, mice showed emergence of two different low-diversity community types, with PAM II mice exhibiting impaired health and a reduced lifespan in later life.
Article
Biology
Joanna L. Gillis, Josephine A. Hinneh, Natalie K. Ryan, Swati Irani, Max Moldovan, Lake-Ee Quek, Raj K. Shrestha, Adrienne R. Hanson, Jianling Xie, Andrew J. Hoy, Jeff Holst, Margaret M. Centenera, Ian G. Mills, David J. Lynn, Luke A. Selth, Lisa M. Butler
Summary: The study reveals a novel link between AR and the pentose phosphate pathway in prostate cancer, with AR indirectly increasing 6PGD expression through SREBP1. Targeting 6PGD with specific inhibitors demonstrated anti-cancer activity by inhibiting PPP, increasing AMPK activity, and reducing AR levels and activity. Co-targeting AR and 6PGD showed greater efficacy in inhibiting prostate cancer cell growth compared to single-agent therapies, suggesting a potential therapeutic strategy.
Review
Oncology
Jianling Xie, Eric P. Kusnadi, Luc Furic, Luke A. Selth
Summary: Estrogen and androgen receptors are key drivers in breast and prostate cancer, regulating mRNA translation to influence cellular protein production and enhance cancer cell growth. Targeting mRNA translation could be a potential strategy for treating breast and prostate cancer.
Review
Biochemistry & Molecular Biology
Xuemin Wang, Christopher G. Proud
Summary: Control of protein synthesis is crucial in shaping the proteome and physiological responses. Phosphorylation of eIF2 and the integrated stress response (ISR) play key roles in regulating protein synthesis. Recent studies have uncovered new features of eIF2 control and the ISR, suggesting potential therapeutic value in interfering with the ISR in certain settings, such as VWM.
BIOCHEMICAL JOURNAL
(2022)
Review
Pharmacology & Pharmacy
Xin Jin, Tingting Qiu, Li Li, Rilei Yu, Xiguang Chen, Changgui Li, Christopher G. Proud, Tao Jiang
Summary: The occurrence of obesity has increased worldwide and contributes to the development of various diseases. Excess energy intake leads to adipocyte hypertrophy, hyperplasia, and visceral fat formation, resulting in cardiovascular and liver diseases. Adipose tissue can secrete adipokines and cytokines, causing insulin resistance and hyperglycemia, exacerbating obesity-related diseases. Although progress has been made in obesity treatment, the progression and pathogenesis of obesity-induced diseases are still unclear. Understanding their links is essential for better management and treatment.
ACTA PHARMACEUTICA SINICA B
(2023)