Phenylethynyl-substituted heterocycles inhibit cyclin D1 and induce the expression of cyclin-dependent kinase inhibitor p21Wif1/Cip1 in colorectal cancer cells

Vitaliy M. Sviripa; Liliia M. Kril; Wen Zhang; Yanqi Xie; Przemyslaw Wyrebek; Larissa Ponomareva; Xifu Liu; Yaxia Yuan; Chang Guo Zhan; David S. Watt; Chunming Liu

doi:10.1039/c7md00393e

Phenylethynyl-substituted heterocycles inhibit cyclin D1 and induce the expression of cyclin-dependent kinase inhibitor p21^Wif1/Cip1 in colorectal cancer cells

Vitaliy M. Sviripa, Liliia M. Kril, Wen Zhang, Yanqi Xie, Przemyslaw Wyrebek, Larissa Ponomareva, Xifu Liu, Yaxia Yuan, Chang Guo Zhan, David S. Watt, Chunming Liu

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

3 Scopus citations

Abstract

Fluorinated phenylethynyl-substituted heterocycles that possessed either an N-methylamino or N,N-dimethylamino group attached to heterocycles including pyridines, indoles, 1H-indazoles, quinolines, and isoquinolines inhibited the proliferation of LS174T colon cancer cells in which the inhibition of cyclin D1 and induction of the cyclin-dependent kinase inhibitor-1 (i.e., p21^Wif1/Cip1) served as readouts for antineoplastic activity at a cellular level. At a molecular level, these agents, particularly 4-((2,6-difluorophenyl)ethynyl)-N-methylisoquinolin-1-amine and 4-((2,6-difluorophenyl)ethynyl)-N,N-dimethylisoquinolin-1-amine, bound and inhibited the catalytic subunit of methionine S-adenosyltransferase-2 (MAT2A).

Original language	English
Pages (from-to)	87-99
Number of pages	13
Journal	MedChemComm
Volume	9
Issue number	1
DOIs	https://doi.org/10.1039/c7md00393e
State	Published - 2018

Bibliographical note

Funding Information:
CL and DSW were supported by CA172379 from the NIH. CGZ was supported by NSF grant CHE-1111761. CL and DSW have partial ownership of a new-start company, Epionc, Inc., that seeks to develop these compounds as commercial agents. CL and DSW disclosed this information and complied with requirements to mitigate any potential conflicts of interest in accord with University of Kentucky policy. DSW was also supported by the Office of the Dean of the College of Medicine, by the Center for Pharmaceutical Research and Innovation in the College of Pharmacy, and by NIH grant number P30 GM110787 from the National Institute of General Medical Sciences to L. Hersh, PI. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or the NIGMS. DSW was also supported by the Office of the Assistant Secretary of Defense for Health Affairs, through the Prostate Cancer Research Program under Award No. W81XWH-16-1-0635. Opinions, interpretations, conclusions and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense.

Publisher Copyright:
© 2018 The Royal Society of Chemistry.

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Pharmacology
Pharmaceutical Science
Drug Discovery
Organic Chemistry

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Access to Document

10.1039/c7md00393e

Cite this

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title = "Phenylethynyl-substituted heterocycles inhibit cyclin D1 and induce the expression of cyclin-dependent kinase inhibitor p21Wif1/Cip1 in colorectal cancer cells",

abstract = "Fluorinated phenylethynyl-substituted heterocycles that possessed either an N-methylamino or N,N-dimethylamino group attached to heterocycles including pyridines, indoles, 1H-indazoles, quinolines, and isoquinolines inhibited the proliferation of LS174T colon cancer cells in which the inhibition of cyclin D1 and induction of the cyclin-dependent kinase inhibitor-1 (i.e., p21Wif1/Cip1) served as readouts for antineoplastic activity at a cellular level. At a molecular level, these agents, particularly 4-((2,6-difluorophenyl)ethynyl)-N-methylisoquinolin-1-amine and 4-((2,6-difluorophenyl)ethynyl)-N,N-dimethylisoquinolin-1-amine, bound and inhibited the catalytic subunit of methionine S-adenosyltransferase-2 (MAT2A).",

author = "Sviripa, {Vitaliy M.} and Kril, {Liliia M.} and Wen Zhang and Yanqi Xie and Przemyslaw Wyrebek and Larissa Ponomareva and Xifu Liu and Yaxia Yuan and Zhan, {Chang Guo} and Watt, {David S.} and Chunming Liu",

note = "Funding Information: CL and DSW were supported by CA172379 from the NIH. CGZ was supported by NSF grant CHE-1111761. CL and DSW have partial ownership of a new-start company, Epionc, Inc., that seeks to develop these compounds as commercial agents. CL and DSW disclosed this information and complied with requirements to mitigate any potential conflicts of interest in accord with University of Kentucky policy. DSW was also supported by the Office of the Dean of the College of Medicine, by the Center for Pharmaceutical Research and Innovation in the College of Pharmacy, and by NIH grant number P30 GM110787 from the National Institute of General Medical Sciences to L. Hersh, PI. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or the NIGMS. DSW was also supported by the Office of the Assistant Secretary of Defense for Health Affairs, through the Prostate Cancer Research Program under Award No. W81XWH-16-1-0635. Opinions, interpretations, conclusions and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense. Publisher Copyright: {\textcopyright} 2018 The Royal Society of Chemistry.",

year = "2018",

doi = "10.1039/c7md00393e",

language = "English",

volume = "9",

pages = "87--99",

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T1 - Phenylethynyl-substituted heterocycles inhibit cyclin D1 and induce the expression of cyclin-dependent kinase inhibitor p21Wif1/Cip1 in colorectal cancer cells

AU - Sviripa, Vitaliy M.

AU - Kril, Liliia M.

AU - Zhang, Wen

AU - Xie, Yanqi

AU - Wyrebek, Przemyslaw

AU - Ponomareva, Larissa

AU - Liu, Xifu

AU - Yuan, Yaxia

AU - Zhan, Chang Guo

AU - Watt, David S.

AU - Liu, Chunming

N1 - Funding Information: CL and DSW were supported by CA172379 from the NIH. CGZ was supported by NSF grant CHE-1111761. CL and DSW have partial ownership of a new-start company, Epionc, Inc., that seeks to develop these compounds as commercial agents. CL and DSW disclosed this information and complied with requirements to mitigate any potential conflicts of interest in accord with University of Kentucky policy. DSW was also supported by the Office of the Dean of the College of Medicine, by the Center for Pharmaceutical Research and Innovation in the College of Pharmacy, and by NIH grant number P30 GM110787 from the National Institute of General Medical Sciences to L. Hersh, PI. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or the NIGMS. DSW was also supported by the Office of the Assistant Secretary of Defense for Health Affairs, through the Prostate Cancer Research Program under Award No. W81XWH-16-1-0635. Opinions, interpretations, conclusions and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense. Publisher Copyright: © 2018 The Royal Society of Chemistry.

PY - 2018

Y1 - 2018

N2 - Fluorinated phenylethynyl-substituted heterocycles that possessed either an N-methylamino or N,N-dimethylamino group attached to heterocycles including pyridines, indoles, 1H-indazoles, quinolines, and isoquinolines inhibited the proliferation of LS174T colon cancer cells in which the inhibition of cyclin D1 and induction of the cyclin-dependent kinase inhibitor-1 (i.e., p21Wif1/Cip1) served as readouts for antineoplastic activity at a cellular level. At a molecular level, these agents, particularly 4-((2,6-difluorophenyl)ethynyl)-N-methylisoquinolin-1-amine and 4-((2,6-difluorophenyl)ethynyl)-N,N-dimethylisoquinolin-1-amine, bound and inhibited the catalytic subunit of methionine S-adenosyltransferase-2 (MAT2A).

AB - Fluorinated phenylethynyl-substituted heterocycles that possessed either an N-methylamino or N,N-dimethylamino group attached to heterocycles including pyridines, indoles, 1H-indazoles, quinolines, and isoquinolines inhibited the proliferation of LS174T colon cancer cells in which the inhibition of cyclin D1 and induction of the cyclin-dependent kinase inhibitor-1 (i.e., p21Wif1/Cip1) served as readouts for antineoplastic activity at a cellular level. At a molecular level, these agents, particularly 4-((2,6-difluorophenyl)ethynyl)-N-methylisoquinolin-1-amine and 4-((2,6-difluorophenyl)ethynyl)-N,N-dimethylisoquinolin-1-amine, bound and inhibited the catalytic subunit of methionine S-adenosyltransferase-2 (MAT2A).

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