Unveiling new chemical scaffolds as Mnk inhibitors

Future Medicinal Chemistry
Sarah DiabShudong Wang

Abstract

The discovery of small molecules that selectively inhibit Mnks is considered of paramount importance towards deciphering the exact role of these proteins in carcinogenesis and to further validate them as anti-cancer drug targets. However, the dearth of structural information of Mnks is a major hurdle. This study unveils the 7H-pyrrolo[2,3-d]pyrimidine derivatives as potent inhibitors of Mnks. ATP and substrate competition assays showed that this scaffold interacts with the ATP binding site, but not with the substrate site. Screened against a panel of cancer cells, Mnk inhibitors were most potent against MV4-11 acute myeloid leukemia cells. The induction of apoptosis was shown to be mediated by downregulation of Mcl-1.

References

Sep 27, 2002·Organic Letters·Jingjun YinJames M McNamara
Apr 20, 2004·Oncogene·Arrigo De Benedetti, Jeremy R Graff
Nov 1, 2006·The Journal of Cell Biology·Biljana CuljkovicKatherine L B Borden
Dec 7, 2007·Genes & Development·Hans-Guido WendelScott W Lowe
Aug 4, 2010·Proceedings of the National Academy of Sciences of the United States of America·Luc FuricNahum Sonenberg
Aug 4, 2010·Proceedings of the National Academy of Sciences of the United States of America·Takeshi UedaTak W Mak
Mar 7, 2012·Oncotarget·Jinqiang HouShudong Wang
Jan 1, 2011·Chemical Science·David S Surry, Stephen L Buchwald
Mar 13, 2014·Chemistry & Biology·Sarah DiabShudong Wang
Nov 29, 2014·Biochemistry·Srinivasaraghavan KannanKassoum Nacro
Feb 17, 2015·Future Medicinal Chemistry·Malika KumarasiriShudong Wang
Jun 6, 2015·Molecular Pharmacology·Theodosia TeoShudong Wang
Aug 14, 2015·Molecular Pharmacology·Sunita K C BasnetShudong Wang

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Citations

Aug 26, 2017·Future Medicinal Chemistry·Ella LinehamSimon J Morley
Apr 29, 2020·International Journal of Molecular Sciences·Celia Pinto-DíezMaría Elena Martín
Jan 15, 2021·Pharmaceutical Patent Analyst·Ahmed M AbdelazizShudong Wang
Nov 13, 2020·Evidence-based Complementary and Alternative Medicine : ECAM·Besufekad AbebeDaniel Bisrat
Aug 1, 2019·Bioorganic & Medicinal Chemistry Letters·Ahmed M AbdelazizShudong Wang
Apr 24, 2021·European Journal of Medicinal Chemistry·Xin JinTao Jiang
Jan 8, 2020·Journal of Medicinal Chemistry·Jacek KwiatkowskiAlvin W Hung
Sep 18, 2021·Journal of Medicinal Chemistry·Weijun XuKassoum Nacro

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Methods Mentioned

BETA
transfection
antisense oligonucleotide
column chromatography
fluorescence resonance energy transfer
fluorescence-activated cell sorting

Software Mentioned

Synergy TM
Topspin

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