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)
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)
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)
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)
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)
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
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
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
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
Oncology
Yulin Xu, Shichong Liao, Lijun Wang, Yuan Wang, Wen Wei, Ke Su, Yi Tu, Shan Zhu
Summary: Galeterone shows potential therapeutic options in targeting breast cancer cells by suppressing MNK-eIF4E and beta-catenin, enhancing the effects of chemotherapeutic drugs, and providing a new direction for the treatment of breast cancer.
CANCER CHEMOTHERAPY AND PHARMACOLOGY
(2021)
Article
Pharmacology & Pharmacy
Xiaolin Yang, Zhenyang Liu, Xianli Yin, Yidong Zeng, Geyang Guo
Summary: Aberrant activation of eIF4E contributes to gastric cancer growth and resistance. Tomivosertib, a dual MNK1/2 inhibitor, enhances the sensitivity of gastric cancer to chemotherapy by suppressing MNK-eIF4E-beta-catenin. This study provides preclinical evidence for clinical trials using tomivosertib in combination with chemotherapy for gastric cancer.
FUNDAMENTAL & CLINICAL PHARMACOLOGY
(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
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
Oncology
Melissa K. Bennett, Manjun Li, Melinda N. Tea, Melissa R. Pitman, John Toubia, Paul P-S Wang, Dovile Anderson, Darren J. Creek, Robert Z. Orlowski, Briony L. Gliddon, Jason A. Powell, Craig T. Wallington-Beddoe, Stuart M. Pitson
Summary: The introduction of the proteasome inhibitor bortezomib has improved patient survival in myeloma, but acquired resistance remains a challenge. Researchers have found that inhibiting sphingolipid metabolism can resensitize bortezomib-resistant myeloma, and this approach also works with other proteasome inhibitors like carfilzomib.
Review
Oncology
Riya Khetan, Cintya Dharmayanti, Todd A. Gillam, Eric Kubler, Manuela Klingler-Hoffmann, Carmela Ricciardelli, Martin K. Oehler, Anton Blencowe, Sanjay Garg, Hugo Albrecht
Summary: This article reviews recent advancements in the targeted delivery of therapeutics to ovarian cancer using nanoparticles and explores the applicability of targeting highly expressed cell surface receptors in ovarian cancer tissue. Targeted nanomedicine strategies have the potential to increase drug accumulation in tumor cells, prevent adverse effects on healthy tissue, and lead to improved patient outcomes.
Article
Biochemistry & Molecular Biology
Biruk Sintayehu Fanta, Laychiluh Mekonnen, Sunita K. C. Basnet, Theodosia Teo, Jimma Lenjisa, Nishat Z. Khair, Lianmeng Kou, Solomon Tadesse, Matthew J. Sykes, Mingfeng Yu, Shudong Wang
Summary: CDK2 deregulation is associated with various human cancers and resistance to anticancer drugs. Bioisosteric replacement of CDKI-73 by a pyrazole group yielded compounds with potent CDK2 inhibition and antiproliferative activity against cancer cell lines. The results highlight the potential of the 2-anilino-4-(1-methyl-1H- pyrazol-4-yl)pyrimidine series in developing selective CDK2 inhibitors for cancer treatment.
BIOORGANIC & MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Renjie Chen, Ramin Hassankhani, Yi Long, Sunita K. C. Basnet, Theodosia Teo, Yuchao Yang, Laychiluh Mekonnen, Mingfeng Yu, Shudong Wang
Summary: In this study, a series of N-pyridinylpyrimidin-2-amines were designed, synthesized, and evaluated, among which one compound was found to be the most potent inhibitor of CDKs 7 and 9 and the most effective anti-proliferative agent against multiple human cancer cell lines.
Review
Pharmacology & Pharmacy
Ava Safaroghli-Azar, Fatemeh Emadi, Jimma Lenjisa, Laychiluh Mekonnen, Shudong Wang
Summary: As the fifth pillar of cancer treatment, immunotherapy has revolutionized therapeutic strategies by focusing on the host's immune system. The discovery of immune-modulatory effects for kinase inhibitors has opened up new possibilities in this approach, as these small molecule inhibitors not only directly target essential proteins for tumor survival and proliferation, but also stimulate immune responses against malignant cells.
DRUG DISCOVERY TODAY
(2023)
Article
Biochemistry & Molecular Biology
Biruk Sintayehu Fanta, Jimma Lenjisa, Theodosia Teo, Lianmeng Kou, Laychiluh Mekonnen, Yuchao Yang, Sunita K. C. Basnet, Ramin Hassankhani, Matthew J. Sykes, Mingfeng Yu, Shudong Wang
Summary: By bioisosteric replacement, a novel series of N,4-di(1H-pyrazol-4-yl)pyrimidin-2-amines were obtained as CDK2 inhibitors. Compound 15 exhibited the most potent CDK2 inhibitory activity with selectivity over other CDKs and showed sub-micromolar antiproliferative activity against cancer cells. This study highlights the potential of N,4-di(1H-pyrazol-4-yl)pyrimidin-2-amine scaffold as potent and selective CDK2 inhibitors for cancer treatment.
Article
Oncology
Saiful Islam, Muhammed H. H. Rahaman, Mingfeng Yu, Benjamin Noll, Jennifer H. H. Martin, Shudong Wang, Richard Head
Summary: Rilpivirine, an anti-viral drug, has been shown to inhibit the growth of leukemia cells and has potential as a treatment for acute myeloid leukemia (AML).
Article
Plant Sciences
Getahun Damissie, Ketema Tolossa, Ariaya Hymete, Solomon Tadesse
Summary: This study aimed to investigate the in vivo antidiarrheal activity of crude extract and coumarins isolated from the roots of Psydrax schimperianus. The results showed that both the crude extract and coumarins exhibited significant antidiarrheal activity.
JOURNAL OF ETHNOPHARMACOLOGY
(2023)
Article
Hematology
Manjun Li, Melissa K. Bennett, John Toubia, Victoria S. Pope, Melinda N. Tea, Sarah Tamang, Michael S. Samuel, Paul H. Anderson, Briony L. Gliddon, Jason A. Powell, Stuart M. Pitson
Summary: This article describes the development of a mouse model of bortezomib-resistant multiple myeloma for the evaluation of new therapeutic approaches.
BRITISH JOURNAL OF HAEMATOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Ebtihal H. Mustafa, Geraldine Laven-Law, Zoya Kikhtyak, Van Nguyen, Simak Ali, Alex A. Pace, Richard Iggo, Alemwork Kebede, Ben Noll, Shudong Wang, Jean M. Winter, Amy R. Dwyer, Wayne D. Tilley, Theresa E. Hickey
Summary: Targeting transcription via CDK9 could be a potential therapeutic strategy for TNBC. Preclinical studies showed that a selective CDK9 inhibitor, CDDD11-8, effectively inhibited proliferation, induced cell cycle arrest, and increased apoptosis of TNBC cells in vitro and in vivo, without apparent toxicity to normal tissues.
Article
Chemistry, Medicinal
Shibin Zhao, Julian Maceren, Mia Chung, Samantha Stone, Raphael Geiben, Melissa L. Boby, Bradley S. Sherborne, Derek S. Tan
Summary: Antibiotic resistance is a major threat to public health, with Gram-negative bacteria presenting unique challenges due to their low permeability and efflux pumps. Limited understanding of the chemical rules for overcoming these barriers hinders antibacterial drug discovery. Efforts to address this issue, such as screening compound libraries and using cheminformatic analysis, have led to the design of sulfamidoadenosines with diverse substituents, showing potential utility in accumulation in Escherichia coli.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Jichun Li, Qing Li, Shuai Xia, Jiahuang Tu, Longbo Zheng, Qian Wang, Shibo Jiang, Chao Wang
Summary: This study successfully developed a short peptide mimetic as a MERS-CoV fusion inhibitor by reproducing the key recognition features of the HR2 helix. The resulting 23-mer lipopeptide showed comparable inhibitory effect to the 36-mer HR2 peptide HR2P-M2. This has important implications for developing short peptide-based antiviral agents to treat MERS-CoV infection.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Krista Jaunsleine, Linda Supe, Jana Spura, Sten van Beek, Anna Sandstrom, Jessica Olsen, Carina Halleskog, Tore Bengtsson, Ilga Mutule, Benjamin Pelcman
Summary: Beta(2)-adrenergic receptor agonists can stimulate glucose uptake by skeletal muscle cells and are therefore potential treatments for type 2 diabetes. The chirality of compounds has a significant impact on the activity of these agonists. This study found that certain synthesized compounds showed higher glucose uptake activity. These findings provide important information for the design of novel beta(2)AR agonists for T2D treatment.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Xin Xu, Jia Chen, Guan Wang, Xiaojuan Zhang, Qiang Li, Xiaobo Zhou, Fengying Guo, Min Li
Summary: The study focuses on EZH2, a promising therapeutic target for various types of cancers. Researchers designed and synthesized a series of novel derivatives aiming to enhance the EZH2 inhibition activity. Among them, compound 28 displayed potent EZH2 inhibition activity and showed high anti-proliferative effects in lymphoma cell lines and xenograft mouse models. The study suggests that compound 28 has potential as a therapeutic candidate for EZH2-associated cancers.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Wei Zhang, Wei Liu, Ya-Dong Zhao, Li-Zi Xing, Ji Xu, Rui-Jun Li, Yun-Xiao Zhang
Summary: This study developed a series of aromatic amide derivatives based on Rhein and investigated their inhibitory activity against alpha-Syn aggregation. Two of these compounds showed promising potential in treating Parkinson's disease by stabilizing alpha-Syn's conformation and disassembling alpha-Syn oligomers and fibrils.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Mani Sharma, S. S. S. S. Sudha Ambadipudi, Neeraj Kumar Chouhan, V. Lakshma Nayak, Srihari Pabbaraja, Sai Balaji Andugulapati, Ramakrishna Sistla
Summary: Therapeutically active lipids in drug delivery systems can enhance the safety and efficacy of treatment. The liposome formulation created using synthesized biologically active lipids showed additive anti-cancer effects and reduced tumorigenic potential.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
