ACS Medicinal Chemistry Letters
Letter
of malignant brain tumors, including brain tumor stem cells. J.
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(6) Pickard, M. R.; Green, A. R.; Ellis, I. O.; Caldas, C.; Hedge, V. L.;
Mourtada-Maarabouni, M.; Williams, G. T. Dysregulated expression of
Fau and MELK is associated with poor prognosis in breast cancer.
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(7) Lin, M.-L.; Park, J.-H.; Toshihiko 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. 2009, 11,
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optimization from 1 to 7 is the significant increase in LE with
molecular size. The availability of multiple protein−ligand
crystal structures enabled a highly efficient optimization process
(∼35 compounds prepared in total), the end result being the
discovery of dual-selective and cell penetrant chemical probe
MELK-T1 7, suitable for the further elucidation of MELK
biology and as a starting point for further optimization.
ASSOCIATED CONTENT
* Supporting Information
■
S
(8) Kuner, R.; Falth, M.; Pressinotti, N. C.; Brase, J. C.; Puig, S. B.;
̈
Assay details; structures of dorsomorphin and OTSSP167;
fragment screen details; crystallographic details and PDB
accession codes; experimental procedures for the preparation
of novel compounds and intermediates. This material is
Metzger, J.; Gade, S.; Schafer, G.; Bartsch, G.; Steiner, E.; Klocker, H.;
̈
̈
Sultmann, H. The maternal embryonic leucine zipper kinase (MELK)
is upregulated in high-grade prostate cancer. J. Mol. Med. 2013, 91,
237−248.
(9) Ryu, B.; Kim, D. S.; DeLuca, A. M.; Alani, R. M. Comprehensive
expression profiling of tumor cell lines identifies molecular signatures
of melanoma progression. PLoS One 2007, 2, e594.
AUTHOR INFORMATION
Corresponding Author
■
(10) Ku, J.-L.; Shin, Y.-K.; Kim, D.-W.; Kim, K.-H.; Choi, J.-S.; Hong,
S.-H.; Jeon, Y.-K.; Kim, S.-H.; Kim, H.-S.; Park, J.-H.; Kim, I.-J.; Park,
J.-G. Establishment and characterization of 13 human colorectal
carcinoma cell lines: mutations of genes and expressions of drug-
sensitivity genes and cancer stem cell markers. Carcinogenesis 2010, 31,
1003−1009.
*(C.N.J.) Tel: 44-1223-226220. Fax: 44-1223-226201. E-mail:
Present Address
§(P.B.) Institut de Chimie Organique et Analytique (ICOA),
(11) Joshi, K.; Banasavadi-Siddegowa, 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, 1051−1063.
Universite
2, France.
́ ́ ́
d’Orleans, UMR CNRS 7311, 45057 Orleans Cedex
Notes
The authors declare no competing financial interest.
(12) 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, 870−881.
(13) 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, 8863−8873.
(14) 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, 1629−1640.
(15) 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,
40003−40011.
(16) Kig, C.; Beullens, M.; Beke, L.; Van Eynde, A.; Linders, J. T. M.;
Brehmer, D.; Bollen, M. Maternal embryonic leucine-zipper kinase
(MELK) reduces replication stress in glioblastoma cells. J. Biol. Chem.
2013, 288, 24223−24233.
(17) Bain, J.; Plater, L.; Elliott, M.; Shapiro, N.; Hastie, C. J.;
Mclaughlan, H.; Klevernic, I.; Arthur, J. S. C.; Alessi, D. R.; Cohen, P.
The selectivity of protein kinase inhibitors: a further update. Biochem.
J. 2007, 408, 297−315.
(18) Fraley, M. E.; Rubino, R. S.; Hoffman, W. F.; Hambaugh, S. R.
Optimization of a pyrazolo[1,5-a]pyrimidine class of KDR kinase
inhibitors: improvements in physical properties enhance cellular
activity and pharmacokinetics. Bioorg. Med. Chem. Lett. 2002, 12,
3537−3541.
(19) Zhou, G.; Myers, R.; Li, Y.; Chen, Y.; Shen, X.; Fenyk-Melody,
J.; Wu, M.; Ventre, J.; Doebber, T.; Fujii, N.; Musi, N.; Hirshman, M.
F.; Goodyear, L. J.; Moller, D. E. Role of AMP-activated protein kinase
in mechanism of metformin action. J. Clin. Invest. 2001, 108, 1167−
1174.
ACKNOWLEDGMENTS
■
We would like to thank Prof. Jan Cools (Catholic University
Leuven, Leuven, Belgium) for the gift of the Ba/F3 Flt3 cell
́
line. We would also like to thank Luis Trabalon (VillaPharma,
Parque tecnologico de Fuente Alamo, Ctra. El Estrecho-
Lobosillo, Km. 2,5-Av. Azul, E-30320 Murcia, Spain) for scale-
up synthesis of compound 7.
ABBREVIATIONS USED
■
DME, 1,2-dimethoxyethane; XPhos, 2-dicyclohexylphosphino-
2′,4′,6′-triisopropylbiphenyl; Pd2dba3, tris(dibenzylidene-
acetone)dipalladium(0)
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dx.doi.org/10.1021/ml5001245 | ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX