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
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
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
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
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
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
Mahmoud Kandeel, Mizuki Yamamoto, Byoung Kwon Park, Abdulla Al-Taher, Aya Watanabe, Jin Gohda, Yasushi Kawaguchi, Kentaro Oh-hashi, Hyung-Joo Kwon, Jun-ichiro Inoue
Summary: A highly potent set of peptides was designed to prevent MERS-CoV fusion through competition with HR2 at its HR1 binding site. These peptides demonstrated strong inhibition of MERS-CoV cell-cell fusion and plaque formation, with no cytotoxic effects at high concentrations, suggesting their potential as promising antiviral agents.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Chemistry, Medicinal
Duncan C. Miller, Suzannah J. Harnor, Mathew P. Martin, Richard A. Noble, Stephen R. Wedge, Celine Cano
Summary: This Miniperspective summarizes the evidence for using the extracellular signal-regulated kinase 5 (ERK5) signaling pathway as a drug target in cancer chemotherapy. It discusses the structure of ERK5 and the evolution of structurally distinct chemotypes of ERK5 kinase domain inhibitors. The complexities of ERK5 pharmacology, including paradoxical ERK5 activation by small molecule inhibitors, are also explored.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Medicine, Research & Experimental
Sujata Jana, Rucha Deo, Rowan P. Hough, Yuzhen Liu, Jessie L. Horn, Jonathan L. Wright, Hung-Ming Lam, Kevin R. Webster, Gary G. Chiang, Nahum Sonenberg, Andrew C. Hsieh
Summary: This study showed that protein synthesis is essential for urothelial cancer formation and growth but not necessary for bladder homeostasis. Phosphorylation of eIF4E at serine 209 plays a critical role in bladder cancer initiation and progression, with tumors having high levels of eIF4E phosphorylation showing sensitivity to specific inhibitors.
Article
Plant Sciences
Enjing Cui, Shihu Qian, Jiaming Li, Xueyang Jiang, Hongwei Wang, Shuaishuai Du, Le Du
Summary: In this study, 26 derivatives of Coixol were designed and synthesized to discover new anti-inflammatory agents. The derivatives containing furan or nitrofuran moieties exhibited stronger anti-inflammatory activity than Coixol and celecoxib, as evidenced by the reduced expression of iNOS, TNF-α, IL-6, and IL-1β. Mechanistic investigations revealed that the inhibition of the NF-κB signaling pathway contributed to the anti-inflammatory effects of 9c and 9j. In vivo studies confirmed their anti-inflammatory activity in a xylene-induced mice auricles edema model.
JOURNAL OF NATURAL PRODUCTS
(2023)
Article
Chemistry, Medicinal
Scott H. Henderson, Fiona Sorrell, James Bennett, Oleg Fedorov, Marcus T. Hanley, Paulo H. Godoi, Roberta Ruela de Sousa, Sean Robinson, Alexander Ashall-Kelly, Iva Hopkins Navratilova, Daryl S. Walter, Jonathan M. Elkins, Simon E. Ward
Summary: DYRK1A plays a crucial role in regulating the proliferation and differentiation of neuronal progenitor cells, making it a potential target for the treatment of neurodegenerative diseases and diabetes. The development of pyrazolo[1,5-b]pyridazin inhibitors with good physicochemical properties and selectivity over the kinome has opened up new possibilities for the discovery of therapies targeting DYRK1A function. Compound 11 demonstrated promising permeability and cellular activity, positioning it as a potential candidate for in vivo studies.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Chemistry, Multidisciplinary
Cindy Schelker, Patrycja Nowak-Sliwinska, Gerrit Borchard
Summary: Fixed-drug combinations have been used for cancer treatment, but current therapies have limitations in terms of resistance and toxicity. The combination of tyrosine kinase inhibitors and histone deacetylase inhibitors is being investigated in clinical trials and has shown promising results. Utilizing appropriate drug delivery systems, such as nanocarriers, can further enhance the activity and specificity of drug combinations. Strategies for the delivery of synergistic drug combinations for cancer treatment are discussed in this review.
JOURNAL OF CONTROLLED RELEASE
(2023)
Review
Biology
Md Lutful Kabir, Feng Wang, Andrew H. A. Clayton
Summary: Cancer is a major global cause of death, and the development of anti-cancer drugs is crucial for combating this disease. However, current drugs face challenges such as side-effects and disease resistance. Spectroscopic methods, particularly fluorescence, can provide important information on drug-target and drug-non-target interactions. Understanding the intrinsic fluorescence of drugs can aid in the development of future drugs with improved side-effects and reduced disease resistance.
Review
Biochemistry & Molecular Biology
Simran Patel, Khushi Sandha, Anushka Waingankar, Prachi Jain, Arundhati Abhyankar
Summary: Atropisomerism plays a significant role in drug discovery and development, especially in modulating the selectivity of inhibitors for cancer therapy. Considering the impact of stereogenic centers in such compounds is necessary for successful cancer drug development.
CHEMICAL BIOLOGY & DRUG DESIGN
(2023)
Article
Oncology
Sathyen A. Prabhu, Omar Moussa, Christophe Goncalves, Judith H. LaPierre, Hsiang Chou, Fan Huang, Vincent R. Richard, Pault Y. M. Ferruzo, Elizabeth M. Guettler, Isabel Soria-Bretones, Laura Kirby, Natascha Gagnon, Jie Su, Jennifer Silvester, Sai Sakktee Krisna, April A. N. Rose, Karen E. Sheppard, David W. Cescon, Frederick A. Mallette, Rene P. Zahedi, Christoph H. Borchers, Sonia V. del Rincon, Wilson H. Miller Jr
Summary: This article investigates the use of CDK4/6 inhibitor palbociclib in melanoma and finds that the treatment induces phosphorylation of eIF4E, leading to increased translation of proteins involved in cell survival and evasion of the drug's antitumor effects.
MOLECULAR CANCER THERAPEUTICS
(2023)
Review
Pharmacology & Pharmacy
Saiful Islam, Shudong Wang, Nikola Bowden, Jennifer Martin, Richard Head
Summary: Repurposing existing non-cancer drugs for cancer therapeutics is an attractive approach to expand clinical pipelines. Systematic identification of repurposing opportunities, such as through commercial drug databases or kinome profiling, can accelerate the advancement of drugs for clinical validation in cancer treatment. Identifying cancer-associated kinase inhibitors and targeting new kinases offer potential for more effective anti-cancer actions.
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
(2022)
Article
Oncology
Abel Tesfaye Anshabo, Laychiluh Bantie, Sarah Diab, Jimma Lenjisa, Alemwork Kebede, Yi Long, Gary Heinemann, Jasmine Karanjia, Benjamin Noll, Sunita K. C. Basnet, Manjun Li, Robert Milne, Hugo Albrecht, Shudong Wang
Summary: CDDD11-8 is an orally bioactive inhibitor of CDK9 that can suppress leukemia cell proliferation and inhibit tumor growth by synergistically inhibiting FLT3. It has the potential to overcome FLT3 inhibition resistance by blocking the upregulation of cancer cell-survival genes.
Article
Chemistry, Medicinal
Mingfeng Yu, Yuchao Yang, Matthew Sykes, Shudong Wang
Summary: Tankyrases are multifunctional enzymes that regulate various biological processes, including telomere maintenance and cellular signaling. Their involvement in human diseases, especially cancer, has led to increased interest in tankyrase inhibitors as potential therapeutics. This review provides an overview of tankyrases and their cancer-related functions, and discusses the progress of small-molecule inhibitors targeting tankyrases, including their binding modes and clinically trialed inhibitors.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Pharmacology & Pharmacy
Theodosia Teo, Sara Kasirzadeh, Hugo Albrecht, Matthew J. Sykes, Yuchao Yang, Shudong Wang
Summary: CDK3 plays a significant role in the cell cycle and is involved in tumorigenesis and cell transformation. However, limited progress has been made in understanding its function due to the lack of selective pharmacological inhibitors.
PHARMACOLOGICAL RESEARCH
(2022)
Article
Chemistry, Medicinal
Saiful Islam, Theodosia Teo, Malika Kumarasiri, Martin Slater, Jennifer H. Martin, Shudong Wang, Richard Head
Summary: The global burden of cancer highlights the need for effective cancer therapies, and one potential approach is the repurposing of existing non-cancer drugs. This study used a combination of in silico and in vitro methods to identify rilpivirine as an Aurora A kinase inhibitor with potential anticancer properties. The results demonstrate the value of integrated screening strategies in identifying repurposed drug candidates for cancer indications.
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
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.
