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1 In Hematological malignancies, MNKs are involved in the oncogenic transformation mainly thorugh eIF4E regulation, as well as through other known and unknown substrates. MNK inhibition has probed to have antitumor effects in these cancers. + 899 word(s) 899 2020-04-24 04:45:17 |
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Pinto-Díez, C.; Ferreras-Martín, R.; Carrión-Marchante, R.; González, V.M.; Martín, M.E. MAP-Kinases Interacting Kinases. Encyclopedia. Available online: (accessed on 13 June 2024).
Pinto-Díez C, Ferreras-Martín R, Carrión-Marchante R, González VM, Martín ME. MAP-Kinases Interacting Kinases. Encyclopedia. Available at: Accessed June 13, 2024.
Pinto-Díez, Celia, Raquel Ferreras-Martín, Rebeca Carrión-Marchante, Víctor M. González, María Elena Martín. "MAP-Kinases Interacting Kinases" Encyclopedia, (accessed June 13, 2024).
Pinto-Díez, C., Ferreras-Martín, R., Carrión-Marchante, R., González, V.M., & Martín, M.E. (2020, April 26). MAP-Kinases Interacting Kinases. In Encyclopedia.
Pinto-Díez, Celia, et al. "MAP-Kinases Interacting Kinases." Encyclopedia. Web. 26 April, 2020.
MAP-Kinases Interacting Kinases

The mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) are involved in oncogenic transformation and can promote metastasis and tumor progression, controlling the expression of specific proteins via eukaryotic initiation factor 4E (eIF4E) regulation, but also through other substrates. In hematological malignancies, which occupy the third place in the global cancer classification, MNK has been demonstrated to participate by regulating the transcription and expression of different proteins. Here is a short summary of the role of MNKs in hematological cancers based on studies conducted to elucidate the mechanism involved in their action, as well as the development of MNK inhibitors.

MNK hematological malignancies eIF4E leukemia lymphoma myeloma MNK inhibitors

1. Introduction

Hematological malignancies as a whole occupy the third place in the global cancer classification, after lung and breast cancer. Among the several hematological cancer types, leukemias, lymphomas, and myelomas are the most frequent [1]

Acute myeloid leukemia (AML) is a genetically heterogeneous, malignant clonal disorder of the hematopoietic system that is characterized by uncontrolled proliferation of immature, abnormal blast cells and impaired production of normal blood cells [2]. In most of the published works, MNK has been demonstrated to be implicated in the pathogenesis of AML. MNK inhibition leads to a decrease in eIF4E phosphorylation levels, which entails antiproliferative effects, cell cycle arrest and an increase in cellular apoptosis mediated by high levels of cleaved PARP and decreasing MCL-1 (myeloid cell leukemia 1) levels. In addition, MNK inhibition has led to the design of new compounds such as MNKI-8e and 8i, pyrimidine analogs, MNKI-4, MNKI-57, merestinib, cercosporamide, BAY1143269, SEL201 or NUCC-54139 [3][4][5][6][7][8][9][10][11][12][13] (Figure 1).


The World Health Organization (WHO) defines chronic myeloid leukemia (CML) as a chronic myeloproliferative neoplasm characterized by the presence of Philadelphia chromosome and the fusion oncogene Bcr-Abl. The inhibition of Bcr-Abl kinase by imatinib results in durable responses in early-stage CML patients, but less in late-stage disease, so patients can develop drug resistance. The joint inhibition of MNK and Bcr-Abl with the MNK inhibitor CGP57380 and with imatinib inhibits polysome assembly, decreasing proliferation and survival [14]. In patients who develop blast crisis (BC-CML), life expectancy is still less than 12 months [15]. The use of imatinib with MNK inhibitors prevents eIF4E phosphorylation in vivo with an antiproliferative effect that could help to combat late-stage disease and to understand other pathways and cellular processes that are dysregulated by Bcr-Abl [14]. In addition, pharmacologic targeting of MNK and mTORC1 kinases, employing rapamycin together with novel MNK inhibitors (MNK1/2 53–54 or MNKI-4 and MNKI-57) or niclosamide (an anthelminthic drug), abolished cell growth by triggering cell apoptotic death and abrogated eIF4E phosphorylation, which may offer a new therapeutic opportunity [16][17][18][19].

Acute lymphocytic leukemia (ALL) consists of the uncontrolled proliferation of an immature cell clone of lymphoid lineage (lymphoblasts) invading the bone marrow and infiltrates multiple organs and tissues. In this type of hematological cancer, it has been described that MNK1 overexpression and phosphorylation activates eIF4E, up-regulating downstream molecules such as MCL-1, c-Myc, survivin and the cyclin-dependent kinase (CDK) 2. MNK1 inhibition with CGP57380 prevents these events and can also overcome eIF4E activation induced by everolimus, sensitizing T-ALL cells to apoptosis [20].

On the other hand, pharmacological inhibition of the Bruton’s tyrosine kinase (BTK) is effective against a variety of B-cell malignancies. In 2016, a dual BTK/MNK inhibitor called QL-X-138 was developed with anti-proliferative effects in vitro and in patient-derived primary cells but for the chronic lymphocytic leukemia (CLL) treatment [21].

2. MAP-Kinases Interacting Kinases in Hematological Cancers

Diffuse large B cell lymphoma (DLBCL) is one of the most common types of lymphoma and accounts for approximately 30%–40% of non-Hodgkin lymphoma cases. It is a fast growing lymphoma with a high proliferation rate and aggressive behavior with a 30% of patients relapsing or refractory to first-line treatment [22]. Most of the MNK inhibitors used in this type of hematological cancer also block eIF4E phosphorylation, as it happens in others. Recently, Reich et al. have discovered an MNK inhibitor, eFT508 that blocked eIF4E phosphorylation and pro-inflammatory cytokine production without affecting proliferation in vitro and in vivo [23]. This inhibitor is being evaluated in a phase II clinical trial in lymphoma. Likewise, Prohibitin (PHB) overexpression is associated with tumor aggressiveness. MNK inhibition by FL3, a synthetic flavagine and ligand of PHBs, determined antitumor activities in vitro and in vivo by inhibiting MNK-dependent eIF4E phosphorylation. This MNK1 inhibition reduced Bcl-2 and c-Myc expression, inducing apoptosis that would allow the treatment of rituximab resistant diseases [24].

Multiple myeloma (MM) is a malignant plasma cell disorder that is characterized by the presence of clonal plasma cell proliferation in bone marrow and over production of monoclonal paraprotein in the blood and/or urine [25]. In 2013, Mehrotra et al. established the regulatory role of MNK pathways as positive effectors in the generation of antineoplastic effects of type I IFNs in myeloproliferative neoplasms (MPNs)[26]. However, it remains to be elucidated whether other downstream effectors of MNK kinases apart from eIF4E are involved in the generation of IFN responses.



  1. Freddie Bray; Jacques Ferlay; Isabelle Soerjomataram; Rebecca L. Siegel; Lindsey A. Torre; Ahmedin Jemal; Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians 2018, 68, 394-424, 10.3322/caac.21492.
  2. Gevorg Tamamyan; Tapan Kadia; Farhad Ravandi; Gautam Borthakur; Jorge Cortes; Elias Jabbour; Naval Daver; Maro Ohanian; Hagop Kantarjian; Marina Konopleva; et al. Frontline treatment of acute myeloid leukemia in adults.. Critical Reviews in Oncology/Hematology 2016, 110, 20-34, 10.1016/j.critrevonc.2016.12.004.
  3. Sarah Diab; Theodosia Teo; Malika Kumarasiri; Peng Li; Mingfeng Yu; Frankie Lam; Sunita Kc Basnet; Matthew James Sykes; Hugo Albrecht; Robert Milne; et al.Shudong Wang Discovery of 5-(2-(Phenylamino)pyrimidin-4-yl)thiazol-2(3H)-one Derivatives as Potent Mnk2 Inhibitors: Synthesis, SAR Analysis and Biological Evaluation. ChemMedChem 2014, 9, 962-972, 10.1002/cmdc.201300552.
  4. Theodosia Teo; Yuchao Yang; Mingfeng Yu; Sunita Kc Basnet; Todd Gillam; Jinqiang Hou; Raffaella M. Schmid; Malika Kumarasiri; Sarah Al Haj Diab; Hugo Albrecht; et al.Matthew James SykesShudong Wang An integrated approach for discovery of highly potent and selective Mnk inhibitors: Screening, synthesis and SAR analysis. European Journal of Medicinal Chemistry 2015, 103, 539-550, 10.1016/j.ejmech.2015.09.008.
  5. Mingfeng Yu; Peng Li; Sunita Kc Basnet; Malika Kumarasiri; Sarah Diab; Theodosia Teo; Hugo Albrecht; Shudong Wang; Discovery of 4-(dihydropyridinon-3-yl)amino-5-methylthieno[2,3-d]pyrimidine derivatives as potent Mnk inhibitors: synthesis, structure–activity relationship analysis and biological evaluation. European Journal of Medicinal Chemistry 2015, 95, 116-126, 10.1016/j.ejmech.2015.03.032.
  6. Benedito A Carneiro; Jason B Kaplan; Jessica K Altman; Francis J Giles; Leonidas C. Platanias; Targeting mTOR signaling pathways and related negative feedback loops for the treatment of acute myeloid leukemia. Cancer Biology & Therapy 2015, 16, 648-656, 10.1080/15384047.2015.1026510.
  7. Ewa M. Kosciuczuk; Aroop K. Kar; Gavin T. Blyth; Mariafausta Fischietti; Sameem Abedin; Alain A. Mina; Rebekah Siliezar; Tomasz Rzymski; Krzysztof Brzozka; Elizabeth A. Eklund; et al.Elspeth M. BeauchampFrank EckerdtDiana SaleiroLeonidas C. Platanias Inhibitory effects of SEL201 in acute myeloid leukemia. Oncotarget 2019, 10, 7112-7121, 10.18632/oncotarget.27388.
  8. Rama K. Mishra; Matthew R. Clutter; Gavin T. Blyth; Ewa M. Kosciuczuk; Amy Z. Blackburn; Elspeth M. Beauchamp; Gary E. Schiltz; Leonidas C. Platanias; Discovery of novel Mnk inhibitors using mutation‐based induced‐fit virtual high‐throughput screening. Chemical Biology & Drug Design 2019, 94, 1813-1823, 10.1111/cbdd.13585.
  9. Sarah Diab; Peng Li; Sunita Kc Basnet; Jingfeng Lu; Mingfeng Yu; Hugo Albrecht; Robert Milne; Shudong Wang; Unveiling new chemical scaffolds as Mnk inhibitors. Future Medicinal Chemistry 2016, 8, 271-285, 10.4155/fmc.15.190.
  10. Jessica K. Altman; Amy Szilard; Bruce W. Konicek; Philip W. Iversen; Barbara Kroczynska; Heather Glaser; Antonella Sassano; Eliza Vakana; Jeremy R. Graff; Leonidas C. Platanias; et al. Inhibition of Mnk kinase activity by cercosporamide and suppressive effects on acute myeloid leukemia precursors. Blood 2013, 121, 3675-3681, 10.1182/blood-2013-01-477216.
  11. Peng Li; Sarah Diab; Mingfeng Yu; Julian Adams; Saiful Islam; Sunita K. C. Basnet; Hugo Albrecht; Robert Milne; Shudong Wang; Inhibition of Mnk enhances apoptotic activity of cytarabine in acute myeloid leukemia cells. Oncotarget 2016, 7, 56811-56825, 10.18632/oncotarget.10796.
  12. Ahmed M. Abdelaziz; Sarah Diab; Saiful Islam; Sunita Kc Basnet; Benjamin Noll; Peng Li; Laychiluh B. Mekonnen; Jingfeng Lu; Hugo Albrecht; Robert Milne; et al.Cobus GerberMingfeng YuShudong WangBen Noll Discovery of N-Phenyl-4-(1H-pyrrol-3-yl)pyrimidin-2-amine Derivatives as Potent Mnk2 Inhibitors: Design, Synthesis, SAR Analysis, and Evaluation of in vitro Anti-leukaemic Activity. Medicinal Chemistry 2019, 15, 602-623, 10.2174/1573406415666181219111511.
  13. Susann Santag; Franziska Siegel; Antje M. Wengner; Claudia Lange; Ulf Bömer; Knut Eis; Florian Pühler; Philip Lienau; Linda Bergemann; Martin Michels; et al.Franz Von NussbaumDominik MumbergKirstin PetersenPress Enter Key For Correspondence Information BAY 1143269, a novel MNK1 inhibitor, targets oncogenic protein expression and shows potent anti-tumor activity. Cancer Letters 2017, 390, 21-29, 10.1016/j.canlet.2016.12.029.
  14. Min Zhang; Wuxia Fu; Sharmila Prabhu; James C. Moore; J. Ko; Jung Woo Kim; Brian J. Druker; Valerie Trapp; John Fruehauf; Hermann Gram; et al.Hung Y. FanS. Tiong Ong Inhibition of Polysome Assembly Enhances Imatinib Activity against Chronic Myelogenous Leukemia and Overcomes Imatinib Resistance. Molecular and Cellular Biology 2008, 28, 6496-6509, 10.1128/mcb.00477-08.
  15. Preetesh Jain; Hagop M. Kantarjian; Ahmad Ghorab; Koji Sasaki; Elias J. Jabbour; Graciela Nogueras Gonzalez; Rashmi Kanagal-Shamanna; Ghayas C. Issa; Guillermo Garcia-Manero; Devendra Kc; et al.Sara DellasalaSherry PierceMarina KonoplevaWilliam G. WierdaSrdan VerstovsekNaval DaverTapan KadiaGautam BorthakurSusan M. O’BrienZeev EstrovFarhad RavandiJorge CortesAhmed GhorabKc Devendra Prognostic factors and survival outcomes in patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era: Cohort study of 477 patients. Cancer 2017, 123, 4391-4402, 10.1002/cncr.30864.
  16. Zhong Liu; Yong Li; Cao Lv; Li Wang; Hongping Song; Anthelmintic drug niclosamide enhances the sensitivity of chronic myeloid leukemia cells to dasatinib through inhibiting Erk/Mnk1/eIF4E pathway. Biochemical and Biophysical Research Communications 2016, 478, 893-899, 10.1016/j.bbrc.2016.08.047.
  17. Theodosia Teo; Mingfeng Yu; Yuchao Yang; Todd Gillam; Frankie Lam; Matthew James Sykes; Shudong Wang; Pharmacologic co-inhibition of Mnks and mTORC1 synergistically suppresses proliferation and perturbs cell cycle progression in blast crisis-chronic myeloid leukemia cells. Cancer Letters 2015, 357, 612-623, 10.1016/j.canlet.2014.12.029.
  18. Joseph Cherian; Kassoum Nacro; Zhi Ying Poh; Samantha Guo; Duraiswamy A. Jeyaraj; Yun Xuan Wong; Melvyn Ho; Hai Yan Yang; Joma Kanikadu Joy; Zekui Perlyn Kwek; et al.Boping LiuJohn Liang Kuan WeeEsther Hq OngMeng Ling ChoongAnders PoulsenMay Ann LeeVishal PendharkarLi Jun DingVithya ManoharanYun Shan ChewKanda SangthongpitagSharon LimS. Tiong OngJeffrey HillThomas H. Keller Structure–Activity Relationship Studies of Mitogen Activated Protein Kinase Interacting Kinase (MNK) 1 and 2 and BCR-ABL1 Inhibitors Targeting Chronic Myeloid Leukemic Cells. Journal of Medicinal Chemistry 2016, 59, 3063-3078, 10.1021/acs.jmedchem.5b01712.
  19. Michal Tomasz Marzec; Xiaobin Liu; Maria Wysocka; Alain H. Rook; Niels Odum; M A Wasik; Simultaneous Inhibition of mTOR-Containing Complex 1 (mTORC1) and MNK Induces Apoptosis of Cutaneous T-Cell Lymphoma (CTCL) Cells. PLOS ONE 2011, 6, e24849, 10.1371/journal.pone.0024849.
  20. Xian-Bo Huang; Chun-Mei Yang; Qing-Mei Han; Xiujin Ye; Wen Lei; Wen-Bin Qian; MNK1 inhibitor CGP57380 overcomes mTOR inhibitor-induced activation of eIF4E: the mechanism of synergic killing of human T-ALL cells. Acta Pharmacologica Sinica 2018, 39, 1894-1901, 10.1038/s41401-018-0161-0.
  21. Hong Wu; Chen Hu; Aoli Wang; Ellen L. Weisberg; Yongfei Chen; Cai-Hong Yun; Wenchao Wang; Yan Liu; Xiaochuan Liu; Bei Tian; et al.Jinhua WangZheng ZhaoYanke LiangBinhua LiLi WangBeilei WangCheng ChenSara J. BuhrlageAtsushi NonamiYuyang LiStacey M. FernandesSophia AdamiaRichard M. StoneIlene A. GalinskyXianhuo WangGuang YangJames D. GriffinJennifer R. BrownMichael J. EckJing LiuNathanael S. GrayQingsong Liu Discovery of a BTK/MNK Dual Inhibitor for Lymphoma and Leukemia. Leukemia 2015, 30, 173-181, 10.1038/leu.2015.180.
  22. Sydney Dubois; Fabrice Jardin; Novel molecular classifications of DLBCL. Nature Reviews Clinical Oncology 2018, 15, 474-476, 10.1038/s41571-018-0041-z.
  23. Siegfried H. Reich; Paul A. Sprengeler; Gary G. Chiang; James R. Appleman; Joan Chen; Jeff Clarine; Boreth Eam; Justin T. Ernst; Qing Han; Vikas K. Goel; et al.Edward Z. R. HanVera HuangIvy N. J. HungAdriana L. JemisonKatti A. JessenJolene MolterDouglas MurphyMelissa NealGregory S. ParkerMichael ShaghafiSamuel SperryJocelyn StauntonCraig R. StumpfPeggy A. ThompsonChinh TranStephen E. WebberChristopher J. WegerskiHong ZhengKevin R. Webster Structure-based Design of Pyridone–Aminal eFT508 Targeting Dysregulated Translation by Selective Mitogen-activated Protein Kinase Interacting Kinases 1 and 2 (MNK1/2) Inhibition. Journal of Medicinal Chemistry 2018, 61, 3516-3540, 10.1021/acs.jmedchem.7b01795.
  24. Hafidha Bentayeb; Marine Aitamer; Barbara Petit; Lydie Dubanet; Sabria Elderwish; Laurent Désaubry; Armand De Gramont; Eric Raymond; Agnès Olivrie; Julie Abraham; et al.Marie-Odile JauberteauDanielle Troutaud Prohibitin (PHB) expression is associated with aggressiveness in DLBCL and flavagline-mediated inhibition of cytoplasmic PHB functions induces anti-tumor effects.. Journal of Experimental & Clinical Cancer Research 2019, 38, 450-15, 10.1186/s13046-019-1440-4.
  25. Arkadiusz Gajek; Anastazja Poczta; Małgorzata Łukawska; Violetta Cecuda- Adamczewska; Joanna Tobiasz; Agnieszka Marczak; Chemical modification of melphalan as a key to improving treatment of haematological malignancies.. Scientific Reports 2020, 10, 4479-14, 10.1038/s41598-020-61436-x.
  26. Swarna Mehrotra; Bhumika Sharma; Sonali Joshi; Barbara Kroczynska; Beata Majchrzak; Brady L. Stein; Brandon McMahon; Jessica K. Altman; Jonathan D. Licht; Darren P. Baker; et al.Elizabeth A. EklundAmittha WickremaAmit VermaEleanor N. FishLeonidas C. Platanias Essential Role for the Mnk Pathway in the Inhibitory Effects of Type I Interferons on Myeloproliferative Neoplasm (MPN) Precursors*. Journal of Biological Chemistry 2013, 288, 23814-23822, 10.1074/jbc.M113.476192.
Subjects: Pathology
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