Selective non-nucleoside inhibitors of human DNA methyltransferases active in cancer including in cancer stem cells

Sergio Valente; Yiwei Liu; Michael Schnekenburger; Clemens Zwergel; Sandro Cosconati; Christina Gros; Maria Tardugno; Donatella Labella; Cristina Florean; Steven Minden; Hideharu Hashimoto; Yanqi Chang; Xing Zhang; Gilbert Kirsch; Ettore Novellino; Paola B. Arimondo; Evelina Miele; Elisabetta Ferretti; Alberto Gulino; Marc Diederich; Xiaodong Cheng; Antonello Mai

doi:10.1021/jm4012627

Selective non-nucleoside inhibitors of human DNA methyltransferases active in cancer including in cancer stem cells

Sergio Valente, Yiwei Liu, Michael Schnekenburger, Clemens Zwergel, Sandro Cosconati, Christina Gros, Maria Tardugno, Donatella Labella, Cristina Florean, Steven Minden, Hideharu Hashimoto, Yanqi Chang, Xing Zhang, Gilbert Kirsch, Ettore Novellino, Paola B. Arimondo, Evelina Miele, Elisabetta Ferretti, Alberto Gulino, Marc DiederichXiaodong Cheng, Antonello Mai^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Research › peer-review

118 Citations (Scopus)

Abstract

DNA methyltransferases (DNMTs) are important enzymes involved in epigenetic control of gene expression and represent valuable targets in cancer chemotherapy. A number of nucleoside DNMT inhibitors (DNMTi) have been studied in cancer, including in cancer stem cells, and two of them (azacytidine and decitabine) have been approved for treatment of myelodysplastic syndromes. However, only a few non-nucleoside DNMTi have been identified so far, and even fewer have been validated in cancer. Through a process of hit-to-lead optimization, we report here the discovery of compound 5 as a potent non-nucleoside DNMTi that is also selective toward other AdoMet-dependent protein methyltransferases. Compound 5 was potent at single-digit micromolar concentrations against a panel of cancer cells and was less toxic in peripheral blood mononuclear cells than two other compounds tested. In mouse medulloblastoma stem cells, 5 inhibited cell growth, whereas related compound 2 showed high cell differentiation. To the best of our knowledge, 2 and 5 are the first non-nucleoside DNMTi tested in a cancer stem cell line.

Original language	English
Pages (from-to)	701-713
Number of pages	13
Journal	Journal of Medicinal Chemistry
Volume	57
Issue number	3
DOIs	https://doi.org/10.1021/jm4012627
Publication status	Published - 13 Feb 2014
Externally published	Yes

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Valente, S., Liu, Y., Schnekenburger, M., Zwergel, C., Cosconati, S., Gros, C., Tardugno, M., Labella, D., Florean, C., Minden, S., Hashimoto, H., Chang, Y., Zhang, X., Kirsch, G., Novellino, E., Arimondo, P. B., Miele, E., Ferretti, E., Gulino, A., ... Mai, A. (2014). Selective non-nucleoside inhibitors of human DNA methyltransferases active in cancer including in cancer stem cells. Journal of Medicinal Chemistry, 57(3), 701-713. https://doi.org/10.1021/jm4012627

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title = "Selective non-nucleoside inhibitors of human DNA methyltransferases active in cancer including in cancer stem cells",

abstract = "DNA methyltransferases (DNMTs) are important enzymes involved in epigenetic control of gene expression and represent valuable targets in cancer chemotherapy. A number of nucleoside DNMT inhibitors (DNMTi) have been studied in cancer, including in cancer stem cells, and two of them (azacytidine and decitabine) have been approved for treatment of myelodysplastic syndromes. However, only a few non-nucleoside DNMTi have been identified so far, and even fewer have been validated in cancer. Through a process of hit-to-lead optimization, we report here the discovery of compound 5 as a potent non-nucleoside DNMTi that is also selective toward other AdoMet-dependent protein methyltransferases. Compound 5 was potent at single-digit micromolar concentrations against a panel of cancer cells and was less toxic in peripheral blood mononuclear cells than two other compounds tested. In mouse medulloblastoma stem cells, 5 inhibited cell growth, whereas related compound 2 showed high cell differentiation. To the best of our knowledge, 2 and 5 are the first non-nucleoside DNMTi tested in a cancer stem cell line.",

author = "Sergio Valente and Yiwei Liu and Michael Schnekenburger and Clemens Zwergel and Sandro Cosconati and Christina Gros and Maria Tardugno and Donatella Labella and Cristina Florean and Steven Minden and Hideharu Hashimoto and Yanqi Chang and Xing Zhang and Gilbert Kirsch and Ettore Novellino and Arimondo, {Paola B.} and Evelina Miele and Elisabetta Ferretti and Alberto Gulino and Marc Diederich and Xiaodong Cheng and Antonello Mai",

year = "2014",

month = feb,

day = "13",

doi = "10.1021/jm4012627",

language = "English",

volume = "57",

pages = "701--713",

journal = "Journal of Medicinal Chemistry",

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Valente, S, Liu, Y, Schnekenburger, M, Zwergel, C, Cosconati, S, Gros, C, Tardugno, M, Labella, D, Florean, C, Minden, S, Hashimoto, H, Chang, Y, Zhang, X, Kirsch, G, Novellino, E, Arimondo, PB, Miele, E, Ferretti, E, Gulino, A, Diederich, M, Cheng, X & Mai, A 2014, 'Selective non-nucleoside inhibitors of human DNA methyltransferases active in cancer including in cancer stem cells', Journal of Medicinal Chemistry, vol. 57, no. 3, pp. 701-713. https://doi.org/10.1021/jm4012627

TY - JOUR

T1 - Selective non-nucleoside inhibitors of human DNA methyltransferases active in cancer including in cancer stem cells

AU - Valente, Sergio

AU - Liu, Yiwei

AU - Schnekenburger, Michael

AU - Zwergel, Clemens

AU - Cosconati, Sandro

AU - Gros, Christina

AU - Tardugno, Maria

AU - Labella, Donatella

AU - Florean, Cristina

AU - Minden, Steven

AU - Hashimoto, Hideharu

AU - Chang, Yanqi

AU - Zhang, Xing

AU - Kirsch, Gilbert

AU - Novellino, Ettore

AU - Arimondo, Paola B.

AU - Miele, Evelina

AU - Ferretti, Elisabetta

AU - Gulino, Alberto

AU - Diederich, Marc

AU - Cheng, Xiaodong

AU - Mai, Antonello

PY - 2014/2/13

Y1 - 2014/2/13

N2 - DNA methyltransferases (DNMTs) are important enzymes involved in epigenetic control of gene expression and represent valuable targets in cancer chemotherapy. A number of nucleoside DNMT inhibitors (DNMTi) have been studied in cancer, including in cancer stem cells, and two of them (azacytidine and decitabine) have been approved for treatment of myelodysplastic syndromes. However, only a few non-nucleoside DNMTi have been identified so far, and even fewer have been validated in cancer. Through a process of hit-to-lead optimization, we report here the discovery of compound 5 as a potent non-nucleoside DNMTi that is also selective toward other AdoMet-dependent protein methyltransferases. Compound 5 was potent at single-digit micromolar concentrations against a panel of cancer cells and was less toxic in peripheral blood mononuclear cells than two other compounds tested. In mouse medulloblastoma stem cells, 5 inhibited cell growth, whereas related compound 2 showed high cell differentiation. To the best of our knowledge, 2 and 5 are the first non-nucleoside DNMTi tested in a cancer stem cell line.

AB - DNA methyltransferases (DNMTs) are important enzymes involved in epigenetic control of gene expression and represent valuable targets in cancer chemotherapy. A number of nucleoside DNMT inhibitors (DNMTi) have been studied in cancer, including in cancer stem cells, and two of them (azacytidine and decitabine) have been approved for treatment of myelodysplastic syndromes. However, only a few non-nucleoside DNMTi have been identified so far, and even fewer have been validated in cancer. Through a process of hit-to-lead optimization, we report here the discovery of compound 5 as a potent non-nucleoside DNMTi that is also selective toward other AdoMet-dependent protein methyltransferases. Compound 5 was potent at single-digit micromolar concentrations against a panel of cancer cells and was less toxic in peripheral blood mononuclear cells than two other compounds tested. In mouse medulloblastoma stem cells, 5 inhibited cell growth, whereas related compound 2 showed high cell differentiation. To the best of our knowledge, 2 and 5 are the first non-nucleoside DNMTi tested in a cancer stem cell line.

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U2 - 10.1021/jm4012627

DO - 10.1021/jm4012627

M3 - Article

C2 - 24387159

AN - SCOPUS:84894065301

SN - 0022-2623

VL - 57

SP - 701

EP - 713

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 3

ER -

Selective non-nucleoside inhibitors of human DNA methyltransferases active in cancer including in cancer stem cells

Abstract

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