Article
Biochemistry & Molecular Biology
Xin-Yu Ke, Ye Chen, Valarie Yu-Yan Tham, Ruby Yu-Tong Lin, Pushkar Dakle, Kassoum Nacro, Mark Edward Puhaindran, Peter Houghton, Angela Pang, Victor Kwanmin Lee, Ling-Wen Ding, Sigal Gery, Jeffrey Hill, Leilei Chen, Liang Xu, H. Phillip Koeffler
Summary: Depletion of MNK1/2 suppresses growth of soft tissue sarcoma cells, and a novel MNK inhibitor ETC-168 shows significant antiproliferative efficacy. Combination of ETC-168 with MCL1 inhibitor exerts synergistic antiproliferative activity against STS cells. This study highlights the potential clinical translation of MNK inhibitors for the treatment of soft tissue sarcoma.
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
Gastroenterology & Hepatology
Amandine Alard, Manon Strehaiano, David Muller, Charline Lasfargues, Stephanie Cassant-Sourdy, Christine Jean, Corinne Bousquet, Yvan Martineau, Stephane Pyronnet
Summary: Despite significant induction of MNK1 kinase activity in acute pancreatitis, preventing eIF4E phosphorylation does not affect the severity of the disease, suggesting that MNK1 acts in acute pancreatitis via another substrate.
Article
Biochemistry & Molecular Biology
Christos Karampelias, Kathleen Watt, Charlotte L. Mattsson, Angel Fernandez Ruiz, Habib Rezanejad, Jiarui Mi, Xiaojing Liu, Lianhe Chu, Jason W. Locasale, Gregory S. Korbutt, Meritxell Rovira, Ola Larsson, Olov Andersson
Summary: This study identifies CID661578 as a small molecule that can induce pancreatic beta-cell regeneration by targeting MNK2 and enhancing protein synthesis. This finding reveals a novel targetable role of MNK2-controlled translation in beta-cell regeneration.
NATURE CHEMICAL BIOLOGY
(2022)
Article
Neurosciences
Stephanie Shiers, James J. Sahn, Theodore J. Price
Summary: Mitogen activated protein kinase interacting kinases (MNK) 1 and 2 play a crucial role in mRNA translation by phosphorylating eukaryotic translation initiation factor (eIF) 4E. They are downstream targets of MAPKs, ERK, and p38. MNKs are involved in sensitizing nociceptors in the DRG and TG, and both MNK1 and MNK2 are expressed in these regions in mice and humans. Our study confirms the expression of MNK1 and MNK2 in human nociceptors, suggesting their potential as therapeutic targets for pain management.
Article
Chemistry, Medicinal
Elisabeth Bou-Petit, Stefan Hummer, Helena Alarcon, Konstantin Slobodnyuk, Marta Cano-Galietero, Pedro Fuentes, Pedro J. Guijarro, Maria Jose Munoz, Leticia Suarez-Cabrera, Anna Santamaria, Roger Estrada-Tejedor, Jose Borrell, Santiago Ramon y Cajal
Summary: Targeting the kinases MNK1 and MNK2 has emerged as a valuable strategy in oncology. Through rational design, a novel core for MNK inhibitors has been identified and validated, which can affect tumor cell growth without impacting normal cells.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Cardiac & Cardiovascular Systems
Bing-Rui Chen, Tian-Wen Wei, Chun-Ping Tang, Jia-Teng Sun, Tian-Kai Shan, Yi Fan, Tong-Tong Yang, Ya-Fei Li, Yao Ma, Si-Bo Wang, Zi-Mu Wang, Hao Wang, Jian-Zhou Shi, Liu Liu, Jia-Wen Chen, Liu-Hua Zhou, Chong Du, Rui Sun, Qi-Ming Wang, Lian-Sheng Wang
Summary: Adult mammals have limited cardiac regeneration potential after injury, while neonatal mouse hearts can completely regenerate within 7 days of birth. This study demonstrated the critical role of mitogen-activated protein kinase-interacting serine/threonine-protein kinase 2 (MNK2) in cardiac regeneration, promoting cardiomyocyte proliferation through activation of the eIF4E-cyclin D1 axis.
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Hong Bu, Xinrui Yuan, Hanshu Wu, Jinpei Zhou, Huibin Zhang
Summary: MNKs are located at the intersection of ERK and p38 MAPK signaling pathways, regulating the translation of mRNA involved in tumor-associated signaling pathways. Synthetic compounds exhibited great inhibitory activity against MNK1/2 and showed anti-proliferative potency against DLBCL cell lines.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Oncology
Qianyu Guo, Margarita Bartish, Christophe Goncalves, Fan Huang, Julian Smith-Voudouris, Sai Sakktee Krisna, Samuel E. J. Preston, Audrey Emond, Vivian Z. Li, Claudia U. Duerr, Yirui Gui, Aurelie Cleret-Buhot, Pamela Thebault, Hanne Lefrere, Liesbeth Lenaerts, Dany Plourde, Jie Su, Barbara C. Mindt, Shannon A. Hewgill, Tiziana Cotechini, Charles C. T. Hindmarch, William Yang, Elie Khoury, Yao Zhan, Valeria Narykina, Yuhong Wei, Giuseppe Floris, Mark Basik, Frederic Amant, Daniela F. Quail, Rejean Lapointe, Jorg H. Fritz, Sonia del Rincon, Wilson H. Miller
Summary: In postpartum breast cancer (PPBC), inhibition of the MNK1/2-eIF4E axis can reduce lung metastasis and impact the tumor and lung immune microenvironment; the repression of IL33 production and enhancing the efficacy of anti-PD-1 immunotherapy by blocking phospho-eIF4E are potential therapeutic approaches.
Article
Medicine, Research & Experimental
Fan Huang, Christophe Goncalves, Margarita Bartish, Joelle Remy-Sarrazin, Mark E. Issa, Brendan Cordeiro, Qianyu Guo, Audrey Emond, Mikhael Attias, William Yang, Dany Plourde, Jie Su, Marina Godoy Gimeno, Yao Zhan, Alba Galan, Tomasz Rzymski, Milena Mazan, Magdalena Masiejczyk, Jacek Faber, Elie Khoury, Alexandre Benoit, Natascha Gagnon, David Dankort, Fabrice Journe, Ghanem E. Ghanem, Connie M. Krawczyk, H. Uri Saragovi, Ciriaco A. Piccirillo, Nahum Sonenberg, Ivan Topisirovic, Christopher E. Rudd, Wilson H. Jr Jr Miller, Sonia del Rincon
Summary: By blocking the MNK1/2-eIF4E axis, the study demonstrated inhibition of melanoma phenotype switching and increased sensitivity to anti-PD-1 immunotherapy in melanoma mouse models. Phospho-eIF4E-deficient melanomas expressed high levels of melanocytic antigens, and genetically ablating phospho-eIF4E reprogrammed the immunosuppressive microenvironment. Dual blockade of MNK1/2-eIF4E and PD-1/PD-L1 immune checkpoint showed efficacy in multiple melanoma models and led to an increase in intratumoral stem-like TCF1(+)PD-1(+)CD8(+) T cells.
JOURNAL OF CLINICAL INVESTIGATION
(2021)
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)
Article
Pharmacology & Pharmacy
Ke Wang, Ziyao Ou, Ge Deng, Shufang Li, Jingjing Su, Yayun Xu, Renpeng Zhou, Wei Hu, Feihu Chen
Summary: The study aimed to explore the possibility of using all-trans retinoic acids (ATRA) in acute myeloid leukemia (AML) and found that ATRA inhibited global translation and protein synthesis in AML cells. The regulatory function of ATRA in translation was essential for its effectiveness in inducing cell growth arrest and differentiation. Transcripts with simple 5 ' UTR gained a translational advantage in AML cells under ATRA stress, and the genes translationally regulated by ATRA were mainly enriched in the PI3K/AKT signaling pathway, which was required for ATRA-induced AML cell differentiation.
Article
Oncology
Retheesh S. Thankan, Elizabeth Thomas, Puranik Purushottamachar, David J. Weber, Vidya P. Ramamurthy, Weiliang Huang, Maureen A. Kane, Vincent C. O. Njar
Summary: TNBC and QNBC, aggressive forms of breast cancer, can be inhibited by VNLG-152R and its deuterated analogs through upregulation of SYVN1 E3 ligase and subsequent degradation of MNK1/2, leading to suppressed tumor growth. These findings were validated in TNBC xenograft models with varying AR expression levels, demonstrating the therapeutic potential of VNLG-152R in treating diverse patient populations with TNBC.
FRONTIERS IN ONCOLOGY
(2023)
Article
Cell Biology
Elizabeth Thomas, Retheesh S. Thankan, Puranik Purushottamachar, Weiliang Huang, Maureen A. Kane, Yuji Zhang, Nicholas P. Ambulos, David J. Weber, Vincent C. O. Njar
Summary: This study investigates the mechanism of action of VNPP433-3 beta and finds that it inhibits prostate cancer through various pathways in both in vitro and in vivo models. It directly binds to AR within the cell and promotes its degradation, as well as decreases the level of MNK1/2 and modulates multiple signaling pathways.
Article
Biochemistry & Molecular Biology
Ali Mehri, Karim Mahnam, Hajar Sirous, Mahmoud Aghaei, Leila Rafiei, Mahboubeh Rostami
Summary: One potential approach for tumor therapy is inhibiting the binding between MDM2 and p53 to reactivate p53 in tumor cells. In this study, Monastrol derivatives were designed as MDM2 inhibitors and evaluated for their cytotoxicity on cancer cells. Compound 5d showed the best inhibitory results in silico and in vitro experiments. These findings suggest that Monastrol derivatives have the potential to be candidates for MDM2 inhibition.
CHEMICAL BIOLOGY & DRUG DESIGN
(2024)