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image of Maternal Embryonic Leucine Zipper Kinase (MELK) as a Promising Therapeutic Target in Triple Negative Breast Cancer

Abstract

Introduction

Maternal Embryonic Leucine Zipper Kinase (MELK) is a serine/threonine protein kinase involved in regulating key cellular processes, including cell cycle progression, apoptosis, embryonic development, spliceosome assembly, and gene expression. Notably, MELK is overexpressed in Triple-Negative Breast Cancer (TNBC), an aggressive malignancy associated with poor prognosis, high drug resistance, and limited treatment options. Given its critical role in TNBC pathogenesis, MELK has emerged as a potential biomarker and therapeutic target. This review explores the molecular functions of MELK, its involvement in oncogenic signaling pathways, and the development of MELK-targeting small-molecule inhibitors.

Methods

A comprehensive literature review was conducted to evaluate current knowledge on MELK, including its molecular functions, interactions within signaling pathways, role in TNBC progression, and potential as a therapeutic target. Relevant databases, including PubMed, Web of Science, Embase, and Scopus, were searched for studies related to MELK expression, signaling mechanisms, and experimental therapeutic approaches.

Results

MELK plays a central role in oncogenic signaling pathways that drive TNBC proliferation and survival. Preclinical studies have demonstrated that MELK inhibition can suppress TNBC cell growth and enhance chemotherapy efficacy. Several small-molecule inhibitors targeting MELK have shown promising anti-tumor activity in preclinical models. However, challenges remain in translating these findings into clinical applications due to drug specificity limitations and resistance mechanisms.

Conclusion

MELK is a promising biomarker and therapeutic target in TNBC. However, further research is required to refine MELK inhibitors, enhance clinical efficacy, and overcome drug resistance mechanisms. Targeting MELK could offer a novel therapeutic strategy to improve TNBC treatment outcomes.

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2025-05-23
2025-09-04

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References

  1. Ganguly R. Mohyeldin A. Thiel J. Kornblum H.I. Beullens M. Nakano I. MELK—a conserved kinase: functions, signaling, cancer, and controversy. Clin. Transl. Med. 2015 4 1 e11 10.1186/s40169‑014‑0045‑y 25852826
    [Google Scholar]
  2. Heyer B.S. Kochanowski H. Solter D. Expression ofMelk, a new protein kinase, during early mouse development. Dev. Dyn. 1999 215 4 344 351 10.1002/(SICI)1097‑0177(199908)215:4<344::AID‑AJA6>3.0.CO;2‑H 10417823
    [Google Scholar]
  3. Beullens M. Vancauwenbergh S. Morrice N. Derua R. Ceulemans H. Waelkens E. Bollen M. Substrate specificity and activity regulation of protein kinase MELK. J. Biol. Chem. 2005 280 48 40003 40011 10.1074/jbc.M507274200 16216881
    [Google Scholar]
  4. Cho Y.S. Kang Y. Kim K. Cha Y. Cho H.S. The crystal structure of MPK38 in complex with OTSSP167, an orally administrative MELK selective inhibitor. Biochem. Biophys. Res. Commun. 2014 447 1 7 11 10.1016/j.bbrc.2014.03.034 24657156
    [Google Scholar]
  5. Wang Y. Lee Y.M. Baitsch L. Huang A. Xiang Y. Tong H. Lako A. Von T. Choi C. Lim E. Min J. Li L. Stegmeier F. Schlegel R. Eck M.J. Gray N.S. Mitchison T.J. Zhao J.J. MELK is an oncogenic kinase essential for mitotic progression in basal-like breast cancer cells. eLife 2014 3 e01763 10.7554/eLife.01763 24844244
    [Google Scholar]
  6. Gray D. Jubb A.M. Hogue D. Dowd P. Kljavin N. Yi S. Bai W. Frantz G. Zhang Z. Koeppen H. de Sauvage F.J. Davis D.P. Maternal embryonic leucine zipper kinase/murine protein serine-threonine kinase 38 is a promising therapeutic target for multiple cancers. Cancer Res. 2005 65 21 9751 9761 10.1158/0008‑5472.CAN‑04‑4531 16266996
    [Google Scholar]
  7. Kohler R.S. Kettelhack H. Knipprath-Mészaros A.M. Fedier A. Schoetzau A. Jacob F. Heinzelmann-Schwarz V. MELK expression in ovarian cancer correlates with poor outcome and its inhibition by OTSSP167 abrogates proliferation and viability of ovarian cancer cells. Gynecol. Oncol. 2017 145 1 159 166 10.1016/j.ygyno.2017.02.016 28214016
    [Google Scholar]
  8. Kuner R. Fälth M. Pressinotti N.C. Brase J.C. Puig S.B. Metzger J. Gade S. Schäfer G. Bartsch G. Steiner E. Klocker H. Sültmann H. The maternal embryonic leucine zipper kinase (MELK) is upregulated in high-grade prostate cancer. J. Mol. Med. (Berl.) 2013 91 2 237 248 10.1007/s00109‑012‑0949‑1 22945237
    [Google Scholar]
  9. Li H. Chen M. Yang Z. Wang Q. Wang J. Jin D. Yang X. Chen F. Zhou X. Luo K. Phillygenin, a MELK Inhibitor, Inhibits Cell Survival and Epithelial–Mesenchymal Transition in Pancreatic Cancer Cells. OncoTargets Ther. 2020 13 2833 2842 10.2147/OTT.S238958 32308417
    [Google Scholar]
  10. Tian J.H. Mu L.J. Wang M.Y. Zeng J. Long Q.Z. Guan B. Wang W. Jiang Y.M. Bai X.J. Du Y.F. BUB1B Promotes Proliferation of Prostate Cancer via Transcriptional Regulation of MELK. Anticancer. Agents Med. Chem. 2020 20 9 1140 1146 10.2174/1871520620666200101141934 31893996
    [Google Scholar]
  11. Nakano I. Masterman-Smith M. Saigusa K. Paucar A.A. Horvath S. Shoemaker L. Watanabe M. Negro A. Bajpai R. Howes A. Lelievre V. Waschek J.A. Lazareff J.A. Freije W.A. Liau L.M. Gilbertson R.J. Cloughesy T.F. Geschwind D.H. Nelson S.F. Mischel P.S. Terskikh A.V. Kornblum H.I. Maternal embryonic leucine zipper kinase is a key regulator of the proliferation of malignant brain tumors, including brain tumor stem cells. J. Neurosci. Res. 2008 86 1 48 60 10.1002/jnr.21471 17722061
    [Google Scholar]
  12. Das A. Prajapati A. Karna A. Sharma H.K. Uppal S. Lather V. Pandita D. Agarwal P. Structure-based virtual screening of chemical libraries as potential MELK inhibitors and their therapeutic evaluation against breast cancer. Chem. Biol. Interact. 2023 376 110443 10.1016/j.cbi.2023.110443 36893906
    [Google Scholar]
  13. Dent R. Trudeau M. Pritchard K.I. Hanna W.M. Kahn H.K. Sawka C.A. Lickley L.A. Rawlinson E. Sun P. Narod S.A. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin. Cancer Res. 2007 13 15 4429 4434 10.1158/1078‑0432.CCR‑06‑3045 17671126
    [Google Scholar]
  14. Zheng C. He G. Deng X. Overview of triple-negative breast cancer. Triple-Negative Breast Cancer 2020 1 20 10.1142/9789813277762_0001
    [Google Scholar]
  15. Lehmann B.D. Pietenpol J.A. Tan A.R. Triple-negative breast cancer: molecular subtypes and new targets for therapy. Am. Soc. Clin. Oncol. Educ. Book 2015 2015 35 e31 e39 10.14694/EdBook_AM.2015.35.e31 25993190
    [Google Scholar]
  16. Reddy K.B. Triple-negative breast cancers: an updated review on treatment options. Curr. Oncol. 2011 18 4 173 179 10.3747/co.v18i4.738 21874107
    [Google Scholar]
  17. McDonald I.M. Graves L.M. Enigmatic MELK: The controversy surrounding its complex role in cancer. J. Biol. Chem. 2020 295 24 8195 8203 10.1074/jbc.REV120.013433 32350113
    [Google Scholar]
  18. Guo B. Godzik A. Reed J.C. Bcl-G, a novel pro-apoptotic member of the Bcl-2 family. J. Biol. Chem. 2001 276 4 2780 2785 10.1074/jbc.M005889200 11054413
    [Google Scholar]
  19. Irshad S. Ellis P. Tutt A. Molecular heterogeneity of triple-negative breast cancer and its clinical implications. Curr. Opin. Oncol. 2011 23 6 566 577 10.1097/CCO.0b013e32834bf8ae 21986848
    [Google Scholar]
  20. Simon M. Mesmar F. Helguero L. Williams C. Genome-wide effects of MELK-inhibitor in triple-negative breast cancer cells indicate context-dependent response with p53 as a key determinant. PLoS One 2017 12 2 e0172832 10.1371/journal.pone.0172832 28235006
    [Google Scholar]
  21. Schmid P. Adams S. Rugo H.S. Schneeweiss A. Barrios C.H. Iwata H. Diéras V. Hegg R. Im S.A. Shaw Wright G. Henschel V. Molinero L. Chui S.Y. Funke R. Husain A. Winer E.P. Loi S. Emens L.A. Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative breast cancer. N. Engl. J. Med. 2018 379 22 2108 2121 10.1056/NEJMoa1809615 30345906
    [Google Scholar]
  22. Rembacz K.P. Zrubek K.M. Golik P. Michalik K. Bogusz J. Wladyka B. Romanowska M. Dubin G. Crystal structure of Maternal Embryonic Leucine Zipper Kinase (MELK) in complex with dorsomorphin (Compound C). Arch. Biochem. Biophys. 2019 671 1 7 10.1016/j.abb.2019.05.014 31108049
    [Google Scholar]
  23. Heinen C. Ács K. Hoogstraten D. Dantuma N.P. C-terminal UBA domains protect ubiquitin receptors by preventing initiation of protein degradation. Nat. Commun. 2011 2 1 191 10.1038/ncomms1179 21304520
    [Google Scholar]
  24. O’Brien M.T. Oakhill J.S. Ling N.X.Y. Langendorf C.G. Hoque A. Dite T.A. Means A.R. Kemp B.E. Scott J.W. Impact of Genetic Variation on Human CaMKK2 Regulation by Ca2+-Calmodulin and Multisite Phosphorylation. Sci. Rep. 2017 7 1 43264 10.1038/srep43264 28230171
    [Google Scholar]
  25. Cao L.S. Wang J. Chen Y. Deng H. Wang Z.X. Wu J.W. Structural basis for the regulation of maternal embryonic leucine zipper kinase. PLoS One 2013 8 7 e70031 10.1371/journal.pone.0070031 23922895
    [Google Scholar]
  26. Janostiak R. Rauniyar N. Lam T.T. Ou J. Zhu L.J. Green M.R. Wajapeyee N. MELK Promotes Melanoma Growth by Stimulating the NF-κB Pathway. Cell Rep. 2017 21 10 2829 2841 10.1016/j.celrep.2017.11.033 29212029
    [Google Scholar]
  27. Cattaneo F. Russo R. Castaldo M. Chambery A. Zollo C. Esposito G. Pedone P.V. Ammendola R. Phosphoproteomic analysis sheds light on intracellular signaling cascades triggered by Formyl-Peptide Receptor 2. Sci. Rep. 2019 9 1 17894 10.1038/s41598‑019‑54502‑6 31784636
    [Google Scholar]
  28. Sun H. Ma H. Zhang H. Ji M. Up-regulation of MELK by E2F1 promotes the proliferation in cervical cancer cells. Int. J. Biol. Sci. 2021 17 14 3875 3888 10.7150/ijbs.62517 34671205
    [Google Scholar]
  29. Vulsteke V. Beullens M. Boudrez A. Keppens S. Van Eynde A. Rider M.H. Stalmans W. Bollen M. Inhibition of spliceosome assembly by the cell cycle-regulated protein kinase MELK and involvement of splicing factor NIPP1. J. Biol. Chem. 2004 279 10 8642 8647 10.1074/jbc.M311466200 14699119
    [Google Scholar]
  30. Bollu L.R. Shepherd J. Zhao D. Ma Y. Tahaney W. Speers C. Mazumdar A. Mills G.B. Brown P.H. Mutant P53 induces MELK expression by release of wild-type P53-dependent suppression of FOXM1. NPJ Breast Cancer 2020 6 1 2 10.1038/s41523‑019‑0143‑5 31909186
    [Google Scholar]
  31. Wang X. Xue X. Pang M. Yu L. Qian J. Li X. Tian M. Lyu A. Lu C. Liu Y. Epithelial–mesenchymal plasticity in cancer: signaling pathways and therapeutic targets. MedComm 2024 5 8 e659 10.1002/mco2.659 39092293
    [Google Scholar]
  32. Sher G. Masoodi T. Patil K. Akhtar S. Kuttikrishnan S. Ahmad A. Uddin S. Dysregulated FOXM1 signaling in the regulation of cancer stem cells. Semin. Cancer Biol. 2022 86 Pt 3 107 121 10.1016/j.semcancer.2022.07.009 35931301
    [Google Scholar]
  33. McDonald I.M. Exploring the Controversial Role of Melk in Cancer. 2020 10.17615/a9ra‑cb39
    [Google Scholar]
  34. So J. Pasculescu A. Dai A.Y. Williton K. James A. Nguyen V. Creixell P. Schoof E.M. Sinclair J. Barrios-Rodiles M. Gu J. Krizus A. Williams R. Olhovsky M. Dennis J.W. Wrana J.L. Linding R. Jorgensen C. Pawson T. Colwill K. Integrative analysis of kinase networks in TRAIL-induced apoptosis provides a source of potential targets for combination therapy. Sci. Signal. 2015 8 371 rs3 10.1126/scisignal.2005700 25852190
    [Google Scholar]
  35. Talloa D. Triarico S. Agresti P. Mastrangelo S. Attinà G. Romano A. Maurizi P. Ruggiero A. BRAF and MEK targeted therapies in pediatric central nervous system tumors. Cancers (Basel) 2022 14 17 4264 10.3390/cancers14174264 36077798
    [Google Scholar]
  36. Heasley L.E. Han S.Y. JNK regulation of oncogenesis. Mol. Cells 2006 21 2 167 173 10.1016/S1016‑8478(23)12876‑7 16682809
    [Google Scholar]
  37. Gu C. Banasavadi-Siddegowda Y.K. Joshi K. Nakamura Y. Kurt H. Gupta S. Nakano I. Tumor-specific activation of the C-JUN/MELK pathway regulates glioma stem cell growth in a p53-dependent manner. Stem Cells 2013 31 5 870 881 10.1002/stem.1322 23339114
    [Google Scholar]
  38. Minata M. Gu C. Joshi K. Nakano-Okuno M. Hong C. Nguyen C.H. Kornblum H.I. Molla A. Nakano I. Multi-kinase inhibitor C1 triggers mitotic catastrophe of glioma stem cells mainly through MELK kinase inhibition. PLoS One 2014 9 4 e92546 10.1371/journal.pone.0092546 24739874
    [Google Scholar]
  39. Joshi K. Banasavadi-Siddegowda Y. Mo X. Kim S.H. Mao P. Kig C. Nardini D. Sobol R.W. Chow L.M.L. Kornblum H.I. Waclaw R. Beullens M. Nakano I. MELK-dependent FOXM1 phosphorylation is essential for proliferation of glioma stem cells. Stem Cells 2013 31 6 1051 1063 10.1002/stem.1358 23404835
    [Google Scholar]
  40. Pickard M.R. Williams G.T. BCL2L14 (BCL2-like 14 (apoptosis facilitator)). Atlas Genet. Cytogenet. Oncol. Haematol. 2014 3 10.4267/2042/53480
    [Google Scholar]
  41. Damaskos C. Garmpi A. Nikolettos K. Vavourakis M. Diamantis E. Patsouras A. Farmaki P. Nonni A. Dimitroulis D. Mantas D. Antoniou E.A. Nikolettos N. Kontzoglou K. Garmpis N. Triple-Negative Breast Cancer: The Progress of Targeted Therapies and Future Tendencies. Anticancer Res. 2019 39 10 5285 5296 10.21873/anticanres.13722 31570423
    [Google Scholar]
  42. Pogoda K. Niwińska A. Murawska M. Pieńkowski T. Analysis of pattern, time and risk factors influencing recurrence in triple-negative breast cancer patients. Med. Oncol. 2013 30 1 388 10.1007/s12032‑012‑0388‑4 23292831
    [Google Scholar]
  43. Yeo W. Treatment Horizons for Triple-negative Breast Cancer. Hong Kong Journal of Radiology 2015 18 2 111 118 10.12809/hkjr1515321
    [Google Scholar]
  44. Xie X. Chauhan G.B. Edupuganti R. Kogawa T. Park J. Tacam M. Tan A.W. Mughees M. Vidhu F. Liu D.D. Taliaferro J.M. Pitner M.K. Browning L.S. Lee J.H. Bertucci F. Shen Y. Wang J. Ueno N.T. Krishnamurthy S. Hortobagyi G.N. Tripathy D. Van Laere S.J. Bartholomeusz G. Dalby K.N. Bartholomeusz C. Maternal Embryonic Leucine Zipper Kinase is Associated with Metastasis in Triple-negative Breast Cancer. Cancer Research Communications 2023 3 6 1078 1092 10.1158/2767‑9764.CRC‑22‑0330 37377604
    [Google Scholar]
  45. Speers C. Zhao S.G. Kothari V. Santola A. Liu M. Wilder-Romans K. Evans J. Batra N. Bartelink H. Hayes D.F. Lawrence T.S. Brown P.H. Pierce L.J. Feng F.Y. Maternal Embryonic Leucine Zipper Kinase (MELK) as a Novel Mediator and Biomarker of Radioresistance in Human Breast Cancer. Clin. Cancer Res. 2016 22 23 5864 5875 10.1158/1078‑0432.CCR‑15‑2711 27225691
    [Google Scholar]
  46. Zhang Y. Zhou X. Li Y. Xu Y. Lu K. Li P. Wang X. Inhibition of maternal embryonic leucine zipper kinase with OTSSP167 displays potent anti-leukemic effects in chronic lymphocytic leukemia. Oncogene 2018 37 41 5520 5533 10.1038/s41388‑018‑0333‑x 29895969
    [Google Scholar]
  47. Hardeman A.A. Han Y.J. Grushko T.A. Mueller J. Gomez M.J. Zheng Y. Olopade O.I. Subtype-specific expression of MELK is partly due to copy number alterations in breast cancer. PLoS One 2022 17 6 e0268693 10.1371/journal.pone.0268693 35749404
    [Google Scholar]
  48. Xu Q. Ge Q. Zhou Y. Yang B. Yang Q. Jiang S. Jiang R. Ai Z. Zhang Z. Teng Y. MELK promotes Endometrial carcinoma progression via activating mTOR signaling pathway. EBioMedicine 2020 51 102609 10.1016/j.ebiom.2019.102609 31915116
    [Google Scholar]
  49. Korde L.A. Somerfield M.R. Carey L.A. Crews J.R. Denduluri N. Hwang E.S. Khan S.A. Loibl S. Morris E.A. Perez A. Regan M.M. Spears P.A. Sudheendra P.K. Symmans W.F. Yung R.L. Harvey B.E. Hershman D.L. Neoadjuvant Chemotherapy, Endocrine Therapy, and Targeted Therapy for Breast Cancer: ASCO Guideline. J. Clin. Oncol. 2021 39 13 1485 1505 10.1200/JCO.20.03399 33507815
    [Google Scholar]
  50. Harger M. Lee J.H. Walker B. Taliaferro J.M. Edupuganti R. Dalby K.N. Ren P. Computational insights into the binding of IN17 inhibitors to MELK. J. Mol. Model. 2019 25 6 151 10.1007/s00894‑019‑4036‑1 31069524
    [Google Scholar]
  51. McDonald I.M. Grant G.D. East M.P. Gilbert T.S.K. Wilkerson E.M. Goldfarb D. Beri J. Herring L.E. Vaziri C. Cook J.G. Emanuele M.J. Graves L.M. Mass spectrometry–based selectivity profiling identifies a highly selective inhibitor of the kinase MELK that delays mitotic entry in cancer cells. J. Biol. Chem. 2020 295 8 2359 2374 10.1074/jbc.RA119.011083 31896573
    [Google Scholar]
  52. Chen S. Zhou Q. Guo Z. Wang Y. Wang L. Liu X. Lu M. Ju L. Xiao Y. Wang X. Inhibition of MELK produces potential anti‐tumour effects in bladder cancer by inducing G1/S cell cycle arrest via the ATM/CHK2/p53 pathway. J. Cell. Mol. Med. 2020 24 2 1804 1821 10.1111/jcmm.14878 31821699
    [Google Scholar]
  53. Chlenski A. Park C. Dobratic M. Salwen H.R. Budke B. Park J.H. Miller R. Applebaum M.A. Wilkinson E. Nakamura Y. Connell P.P. Cohn S.L. Maternal Embryonic Leucine Zipper Kinase (MELK), a Potential Therapeutic Target for Neuroblastoma. Mol. Cancer Ther. 2019 18 3 507 516 10.1158/1535‑7163.MCT‑18‑0819 30674566
    [Google Scholar]
  54. Chung S. Suzuki H. Miyamoto T. Takamatsu N. Tatsuguchi A. Ueda K. Kijima K. Nakamura Y. Matsuo Y. Development of an orally-administrative MELK-targeting inhibitor that suppresses the growth of various types of human cancer. Oncotarget 2012 3 12 1629 1640 10.18632/oncotarget.790 23283305
    [Google Scholar]
  55. Tang R. Gai Y. Li K. Hu F. Gong C. Wang S. Feng F. Altine B. Hu J. Lan X. A novel carbon-11 radiolabeled maternal embryonic leucine zipper kinase inhibitor for PET imaging of triple-negative breast cancer. Bioorg. Chem. 2021 107 104609 10.1016/j.bioorg.2020.104609 33454507
    [Google Scholar]
  56. Hu F. Gong C. Gai Y. Jiang D. Liu Q. Wang S. Hu M. Pi R. Shu H. Hu J. Lan X. [ 18 F]F-ET-OTSSP167 Targets Maternal Embryo Leucine Zipper Kinase for PET Imaging of Triple-Negative Breast Cancer. Mol. Pharm. 2021 18 9 3544 3552 10.1021/acs.molpharmaceut.1c00454 34482695
    [Google Scholar]
  57. Bridges C.S. Chen T.J. Puppi M. Rabin K.R. Lacorazza H.D. Antileukemic properties of the kinase inhibitor OTSSP167 in T-cell acute lymphoblastic leukemia. Blood Adv. 2023 7 3 422 435 10.1182/bloodadvances.2022008548 36399528
    [Google Scholar]
  58. Tang B. Zhu J. Fang S. Wang Y. Vinothkumar R. Li M. Weng Q. zheng L. Yang Y. Qiu R. Xu M. Zhao Z. Ji J. Pharmacological inhibition of MELK restricts ferroptosis and the inflammatory response in colitis and colitis-propelled carcinogenesis. Free Radic. Biol. Med. 2021 172 312 329 10.1016/j.freeradbiomed.2021.06.012 34144192
    [Google Scholar]
  59. Hoang T.M.N. Favier B. Valette A. Barette C. Nguyen C.H. Lafanechère L. Grierson D.S. Dimitrov S. Molla A. Benzo[e]pyridoindoles, novel inhibitors of the Aurora kinases. Cell Cycle 2009 8 5 765 772 10.4161/cc.8.5.7879 19221479
    [Google Scholar]
  60. Ganguly R. Hong C.S. Smith L.G.F. Kornblum H.I. Nakano I. Maternal embryonic leucine zipper kinase: key kinase for stem cell phenotype in glioma and other cancers. Mol. Cancer Ther. 2014 13 6 1393 1398 10.1158/1535‑7163.MCT‑13‑0764 24795222
    [Google Scholar]
  61. Gauthier A. Ho M. Role of sorafenib in the treatment of advanced hepatocellular carcinoma: An update. Hepatol. Res. 2013 43 2 147 154 10.1111/j.1872‑034X.2012.01113.x 23145926
    [Google Scholar]
  62. Shiseki M. Yoshida C. Takezako N. Ohwada A. Kumagai T. Nishiwaki K. Horikoshi A. Fukuda T. Takano H. Kouzai Y. Tanaka J. Morita S. Sakamoto J. Sakamaki H. Inokuchi K. Dasatinib rapidly induces deep molecular response in chronic-phase chronic myeloid leukemia patients who achieved major molecular response with detectable levels of BCR-ABL1 transcripts by imatinib therapy. Int. J. Clin. Oncol. 2017 22 5 972 979 10.1007/s10147‑017‑1141‑y 28550414
    [Google Scholar]
  63. Banerjee S. Phosphorylation, ubiquitylation and characterisation of specific inhibitors of AMPK-related kinase NUAK1/ARK5. (Doctoral Thesis). University of Dundee. 2013
    [Google Scholar]
  64. Yoon C-H. Kim M-J. Kim R-K. Lim E-J. Choi K-S. An S. Hwang S-G. Kang S-G. Suh Y. Park M-J. Lee S-J. c-Jun N-terminal kinase has a pivotal role in the maintenance of self-renewal and tumorigenicity in glioma stem-like cells. Oncogene 2012 31 44 4655 4666 10.1038/onc.2011.634 22249269
    [Google Scholar]
  65. Bennett B.L. Sasaki D.T. Murray B.W. O’Leary E.C. Sakata S.T. Xu W. Leisten J.C. Motiwala A. Pierce S. Satoh Y. Bhagwat S.S. Manning A.M. Anderson D.W. SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc. Natl. Acad. Sci. USA 2001 98 24 13681 13686 10.1073/pnas.251194298 11717429
    [Google Scholar]
  66. Madureira P.A. Varshochi R. Constantinidou D. Francis R.E. Coombes R.C. Yao K.M. Lam E.W.F. The Forkhead box M1 protein regulates the transcription of the estrogen receptor α in breast cancer cells. J. Biol. Chem. 2006 281 35 25167 25176 10.1074/jbc.M603906200 16809346
    [Google Scholar]
  67. Zhang X. Wang J. Wang Y. Liu G. Li H. Yu J. Wu R. Liang J. Yu R. Liu X. MELK Inhibition Effectively Suppresses Growth of Glioblastoma and Cancer Stem-Like Cells by Blocking AKT and FOXM1 Pathways. Front. Oncol. 2021 10 608082 10.3389/fonc.2020.608082 33520717
    [Google Scholar]
  68. Edupuganti R. Taliaferro J.M. Wang Q. Xie X. Cho E.J. Vidhu F. Ren P. Anslyn E.V. Bartholomeusz C. Dalby K.N. Discovery of a potent inhibitor of MELK that inhibits expression of the anti-apoptotic protein Mcl-1 and TNBC cell growth. Bioorg. Med. Chem. 2017 25 9 2609 2616 10.1016/j.bmc.2017.03.018 28351607
    [Google Scholar]
  69. Beke L. Kig C. Linders J.T.M. Boens S. Boeckx A. van Heerde E. Parade M. De Bondt A. Van den Wyngaert I. Bashir T. Ogata S. Meerpoel L. Van Eynde A. Johnson C.N. Beullens M. Brehmer D. Bollen M. MELK-T1, a small-molecule inhibitor of protein kinase MELK, decreases DNA-damage tolerance in proliferating cancer cells. Biosci. Rep. 2015 35 6 e00267 10.1042/BSR20150194 26431963
    [Google Scholar]
  70. Xiao Y. Nimmer P. Sheppard G.S. Bruncko M. Hessler P. Lu X. Roberts-Rapp L. Pappano W.N. Elmore S.W. Souers A.J. Leverson J.D. Phillips D.C. MCL-1 Is a Key Determinant of Breast Cancer Cell Survival: Validation of MCL-1 Dependency Utilizing a Highly Selective Small Molecule Inhibitor. Mol. Cancer Ther. 2015 14 8 1837 1847 10.1158/1535‑7163.MCT‑14‑0928 26013319
    [Google Scholar]
  71. Touré B.B. Giraldes J. Smith T. Sprague E.R. Wang Y. Mathieu S. Chen Z. Mishina Y. Feng Y. Yan-Neale Y. Shakya S. Chen D. Meyer M. Puleo D. Brazell J.T. Straub C. Sage D. Wright K. Yuan Y. Chen X. Duca J. Kim S. Tian L. Martin E. Hurov K. Shao W. Toward the Validation of Maternal Embryonic Leucine Zipper Kinase: Discovery, Optimization of Highly Potent and Selective Inhibitors, and Preliminary Biology Insight. J. Med. Chem. 2016 59 10 4711 4723 10.1021/acs.jmedchem.6b00052 27187609
    [Google Scholar]
  72. Rácz A. Palkó R. Csányi D. Riedl Z. Bajusz D. Keserű G.M. Consensus Virtual Screening Identified (1,2,4)Triazolo(1,5‐b)isoquinolines As MELK Inhibitor Chemotypes. ChemMedChem 2021 17 2 e202100569 10.1002/cmdc.202100569 34632716
    [Google Scholar]
  73. Rachman M. Bajusz D. Hetényi A. Scarpino A. Merő B. Egyed A. Buday L. Barril X. Keserű G.M. Discovery of a novel kinase hinge binder fragment by dynamic undocking. RSC Medicinal Chemistry 2020 11 5 552 558 10.1039/C9MD00519F 33479656
    [Google Scholar]
  74. Hebbard L.W. Maurer J. Miller A. Lesperance J. Hassell J. Oshima R.G. Terskikh A.V. Maternal embryonic leucine zipper kinase is upregulated and required in mammary tumor-initiating cells in vivo. Cancer Res. 2010 70 21 8863 8873 10.1158/0008‑5472.CAN‑10‑1295 20861186
    [Google Scholar]
  75. Beke L. Linders J.T. Kig C. Boeckx A. Heerde E. Wuyts D. Parade M. Meerpoel L. Johnson C. Beullens M. Bollen M. Brehmer D. Abstract 2936: JNJ-47117096, a selective small molecule inhibitor of the MELK oncogene decreases DNA damage tolerance in highly proliferating cancer cells. Cancer Res. 2014 74 19_Supplement 2936 10.1158/1538‑7445.AM2014‑2936
    [Google Scholar]
  76. Sun Y. Liu X. He Q. Zhang N. Yan W. Lv X. Wang Y. Discovery of first-in-class PROTACs targeting maternal embryonic leucine zipper kinase (MELK) for the treatment of Burkitt lymphoma. RSC Medicinal Chemistry 2024 15 7 2351 2356 10.1039/D4MD00252K 39026635
    [Google Scholar]
  77. Ji W. Arnst C. Tipton A.R. Bekier M.E. II Taylor W.R. Yen T.J. Liu S.T. OTSSP167 Abrogates Mitotic Checkpoint through Inhibiting Multiple Mitotic Kinases. PLoS One 2016 11 4 e0153518 10.1371/journal.pone.0153518 27082996
    [Google Scholar]
  78. Huang H.T. Seo H.S. Zhang T. Wang Y. Jiang B. Li Q. Buckley D.L. Nabet B. Roberts J.M. Paulk J. Dastjerdi S. Winter G.E. McLauchlan H. Moran J. Bradner J.E. Eck M.J. Dhe-Paganon S. Zhao J.J. Gray N.S. MELK is not necessary for the proliferation of basal-like breast cancer cells. eLife 2017 6 e26693 10.7554/eLife.26693 28926338
    [Google Scholar]
  79. Giuliano C.J. Lin A. Smith J.C. Palladino A.C. Sheltzer J.M. Abstract 837A: Combining CRISPR/Cas9 mutagenesis and a small-molecule inhibitor to probe the function of MELK in cancer. Cancer Res. 2018 78 13_Supplement 837A 10.1158/1538‑7445.AM2018‑837A
    [Google Scholar]
  80. Zwang Y. Jonas O. Chen C. Rinne M.L. Doench J.G. Piccioni F. Tan L. Huang H.T. Wang J. Ham Y.J. O’Connell J. Bhola P. Doshi M. Whitman M. Cima M. Letai A. Root D.E. Langer R.S. Gray N. Hahn W.C. Synergistic interactions with PI3K inhibition that induce apoptosis. eLife 2017 6 e24523 10.7554/eLife.24523 28561737
    [Google Scholar]
  81. Huang H. Exploring novel kinase targets and novel pharmacology for cancer therapeutics. Harvard University 2017
    [Google Scholar]
  82. Jaune E. Cavazza E. Ronco C. Grytsai O. Abbe P. Tekaya N. Zerhouni M. Beranger G. Kaminski L. Bost F. Gesson M. Tulic M. Hofman P. Ballotti R. Passeron T. Botton T. Benhida R. Rocchi S. Discovery of a new molecule inducing melanoma cell death: dual AMPK/MELK targeting for novel melanoma therapies. Cell Death Dis. 2021 12 1 64 10.1038/s41419‑020‑03344‑6 33431809
    [Google Scholar]
  83. Klaeger S. Heinzlmeir S. Wilhelm M. Polzer H. Vick B. Koenig P.A. Reinecke M. Ruprecht B. Petzoldt S. Meng C. Zecha J. Reiter K. Qiao H. Helm D. Koch H. Schoof M. Canevari G. Casale E. Depaolini S.R. Feuchtinger A. Wu Z. Schmidt T. Rueckert L. Becker W. Huenges J. Garz A.K. Gohlke B.O. Zolg D.P. Kayser G. Vooder T. Preissner R. Hahne H. Tõnisson N. Kramer K. Götze K. Bassermann F. Schlegl J. Ehrlich H.C. Aiche S. Walch A. Greif P.A. Schneider S. Felder E.R. Ruland J. Médard G. Jeremias I. Spiekermann K. Kuster B. The target landscape of clinical kinase drugs. Science 2017 358 6367 eaan4368 10.1126/science.aan4368 29191878
    [Google Scholar]
  84. Suman S. Suman G. Mishra S. Current Advances in Breast Cancer Research: A Molecular Approach. Bentham Science Publishers 2020 10.2174/97898114514471200101
    [Google Scholar]
  85. Lin M.L. Park J.H. Nishidate T. Nakamura Y. Katagiri T. Involvement of maternal embryonic leucine zipper kinase (MELK) in mammary carcinogenesis through interaction with Bcl-G, a pro-apoptotic member of the Bcl-2 family. Breast Cancer Res. 2007 9 1 R17 10.1186/bcr1650 17280616
    [Google Scholar]
  86. Nakamura Y. Katagiri T. Nakatsuru S. Breast cancer-associated gene, MELK, and its interactions with Bcl-G. WO patent 2008/023841 2008
  87. Calcagno D.Q. Takeno S.S. Gigek C.O. Leal M.F. Wisnieski F. Chen E.S. Araújo T.M.T. Lima E.M. Melaragno M.I. Demachki S. Assumpção P.P. Burbano R.R. Smith M.C. Identification of IL11RA and MELK amplification in gastric cancer by comprehensive genomic profiling of gastric cancer cell lines. World J. Gastroenterol. 2016 22 43 9506 9514 10.3748/wjg.v22.i43.9506 27920471
    [Google Scholar]
  88. Lee H.G. Song E.Y. Kang M.A. Kim J.T. Kim J.W. Yeom Y.I. Kim S.Y. Park K.C. CST1, DCC1, IFITM1 or MELK as markers for diagnosing stomach cancer. US 9,075,066 B2 2015
  89. Van Cutsem E. Cervantes A. Nordlinger B. Arnold D. Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2014 25 iii1 iii9 10.1093/annonc/mdu260 25190710
    [Google Scholar]
  90. Ezz Eldin R.R. Al-Karmalawy A.A. Alotaibi M.H. Saleh M.A. Quinoxaline derivatives as a promising scaffold for breast cancer treatment. New J. Chem. 2022 46 21 9975 9984 10.1039/D2NJ00050D
    [Google Scholar]
  91. Jurmeister S. Ramos-Montoya A. Sandi C. Pértega-Gomes N. Wadhwa K. Lamb A.D. Dunning M.J. Attig J. Carroll J.S. Fryer L.G.D. Felisbino S.L. Neal D.E. Identification of potential therapeutic targets in prostate cancer through a cross‐species approach. EMBO Mol. Med. 2018 10 3 e8274 10.15252/emmm.201708274 29437778
    [Google Scholar]
  92. Lawal H.A. Uzairu A. Uba S. QSAR, molecular docking studies, ligand-based design and pharmacokinetic analysis on Maternal Embryonic Leucine Zipper Kinase (MELK) inhibitors as potential anti-triple-negative breast cancer (MDA-MB-231 cell line) drug compounds. Bull. Natl. Res. Cent. 2021 45 1 90 10.1186/s42269‑021‑00541‑x
    [Google Scholar]
  93. Allegretti P.A. Horton T.M. Abdolazimi Y. Moeller H.P. Yeh B. Caffet M. Michel G. Smith M. Annes J.P. Generation of highly potent DYRK1A-dependent inducers of human β-Cell replication via Multi-Dimensional compound optimization. Bioorg. Med. Chem. 2020 28 1 115193 10.1016/j.bmc.2019.115193 31757680
    [Google Scholar]
  94. Ansari A. Ali A. Asif M. Shamsuzzaman S. Review: biologically active pyrazole derivatives. New J. Chem. 2017 41 1 16 41 10.1039/C6NJ03181A
    [Google Scholar]
  95. Talele T.T. Acetylene Group, Friend or Foe in Medicinal Chemistry. J. Med. Chem. 2020 63 11 5625 5663 10.1021/acs.jmedchem.9b01617 32031378
    [Google Scholar]
  96. Meel M.H. de Gooijer M.C. Guillén Navarro M. Waranecki P. Breur M. Buil L.C.M. Wedekind L.E. Twisk J.W.R. Koster J. Hashizume R. Raabe E.H. Montero Carcaboso A. Bugiani M. van Tellingen O. van Vuurden D.G. Kaspers G.J.L. Hulleman E. MELK Inhibition in Diffuse Intrinsic Pontine Glioma. Clin. Cancer Res. 2018 24 22 5645 5657 10.1158/1078‑0432.CCR‑18‑0924 30061363
    [Google Scholar]
  97. Oshi M. Gandhi S. Huyser M.R. Tokumaru Y. Yan L. Yamada A. Matsuyama R. Endo I. Takabe K. MELK expression in breast cancer is associated with infiltration of immune cell and pathological compete response (pCR) after neoadjuvant chemotherapy. Am. J. Cancer Res. 2021 11 9 4421 4437 34659896
    [Google Scholar]
  98. Katz J.D. Jewell J.P. Guerin D.J. Lim J. Dinsmore C.J. Deshmukh S.V. Pan B.S. Marshall C.G. Lu W. Altman M.D. Dahlberg W.K. Davis L. Falcone D. Gabarda A.E. Hang G. Hatch H. Holmes R. Kunii K. Lumb K.J. Lutterbach B. Mathvink R. Nazef N. Patel S.B. Qu X. Reilly J.F. Rickert K.W. Rosenstein C. Soisson S.M. Spencer K.B. Szewczak A.A. Walker D. Wang W. Young J. Zeng Q. Discovery of a 5 H -Benzo[4,5]cyclohepta[1,2- b ]pyridin-5-one (MK-2461) Inhibitor of c-Met Kinase for the Treatment of Cancer. J. Med. Chem. 2011 54 12 4092 4108 10.1021/jm200112k 21608528
    [Google Scholar]
  99. Lee I.H. Lee S.J. Kang B. Lee J. Jung J.H. Park H.Y. Park J.Y. Park N.J.Y. Kim E.A. Kang J. Chae Y.S. Exploration of MELK as a downstream of Del-1 and druggable targets in triple-negative breast cancer. Breast Cancer Res. Treat. 2024 205 1 181 191 10.1007/s10549‑023‑07198‑2 38279017
    [Google Scholar]
  100. Badouel C. Körner R. Frank-Vaillant M. Couturier A. Nigg E.A. Tassan J.P. M-phase MELK activity is regulated by MPF and MAPK. Cell Cycle 2006 5 8 883 889 10.4161/cc.5.8.2683 16628004
    [Google Scholar]
  101. Chung S. Kijima K. Kudo A. Fujisawa Y. Harada Y. Taira A. Takamatsu N. Miyamoto T. Matsuo Y. Nakamura Y. Preclinical evaluation of biomarkers associated with antitumor activity of MELK inhibitor. Oncotarget 2016 7 14 18171 18182 10.18632/oncotarget.7685 26918358
    [Google Scholar]
  102. Safa A.R. Resistance to cell death and its modulation in cancer stem cells. Crit. Rev. Oncog. 2016 21 3-4 203 219 10.1615/CritRevOncog.2016016976 27915972
    [Google Scholar]
/content/journals/acamc/10.2174/0118715206389899250522091159
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Maternal Embryonic Leucine Zipper Kinase (MELK) as a Promising Therapeutic Target in Triple Negative Breast Cancer
Bentham Science Publishers ; https://doi.org/10.2174/0118715206389899250522091159
/content/journals/acamc/10.2174/0118715206389899250522091159
/content/journals/acamc/10.2174/0118715206389899250522091159
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  • Article Type:     Review Article
Keywords: apoptosis ; Cancer progression ; targeted therapy ; AMPK ; MELK ; Bcl‐2 ; TNBC

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