Synthesis and in vitro evaluation of biotinylated RG108: a high affinity compound for studying binding interactions with human DNA methyltransferases

Bioconjugate Chemistry
Esther SchirrmacherRalf Schirrmacher

Abstract

Small-molecule inhibitors of DNA methyltransferases such as RG108 represent promising candidates for cancer drug development. We report the synthesis and in vitro analysis of a biotinylated RG108 conjugate, 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(5-[3-[5-(2-oxo-hexahydro-thieno[3,4-d]imidazol-4-yl)pentanoylamino]propoxy]-1H-indol-3-yl)propionic acid (bio-RG108), for the evaluation of interactions with DNA methyltransferase enzymes. The structural design of the chemically modified inhibitor was aided by molecular modeling, which suggested the possibility for extensive chemical modifications at the 5-position of the tryptophan moiety in RG108. The inhibitory activity of the corresponding derivative was confirmed in a cell-free biochemical assay, where bio-RG108 showed an undiminished inhibition of DNA methyltransferase activity (IC50 = 40 nM). Bio-RG108 therefore represents a suitable bioconjugate for the elucidation of inhibitory mechanisms and for the affinity purification of RG108-associated proteins.

References

May 5, 2000·Biomolecular Engineering·H Schetters
Jan 10, 2002·Genes & Development·Adrian Bird
Feb 25, 2003·Chemphyschem : a European Journal of Chemical Physics and Physical Chemistry·Jan RichterChristof M Niemeyer
Mar 20, 2003·Journal of the American Chemical Society·Yossi WeizmannItamar Willner
Nov 13, 2003·Journal of the American Chemical Society·K K CaswellCatherine J Murphy
Oct 20, 2005·Journal of the National Cancer Institute·Frank Lyko, Robert Brown
Jan 20, 2006·Journal of Medicinal Chemistry·Pawel SiedleckiPiotr Zielenkiewicz

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Citations

Jun 11, 2011·Journal of Computer-aided Molecular Design·Jakyung Yoo, José L Medina-Franco
Aug 3, 2013·Biochemical and Biophysical Research Communications·Hyehyeon LeeKyung Lib Jang
Aug 27, 2013·Nature Neuroscience·Jeremy J DayJ David Sweatt
Oct 17, 2008·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Farah D LubinJ David Sweatt
May 13, 2014·Integrative and Comparative Biology·Sebastian AlvaradoMoshe Szyf
Mar 21, 2013·Molecular BioSystems·Yukihiro ItohNaoki Miyata
Mar 9, 2011·Expert Opinion on Investigational Drugs·Ernesto VignaFortunato Morabito
Sep 16, 2008·The International Journal of Biochemistry & Cell Biology·Antonello Mai, Lucia Altucci
May 15, 2012·Medicinal Research Reviews·Junyan LuKeqin Kathy Li
Mar 3, 2010·European Journal of Haematology·Caterina MusolinoAlessandro Allegra
Jul 16, 2008·Expert Opinion on Therapeutic Targets·Paula A AbreuHelena C Castro
Jul 8, 2015·Clinical and Experimental Medicine·Valerio PazienzaAngelo Andriulli
May 23, 2015·Nature Reviews. Drug Discovery·Moshe Szyf
Oct 30, 2012·Molecular Oncology·Angela NebbiosoLucia Altucci
Dec 23, 2014·Epigenomics·Raymond Lo, Rosanna Weksberg
Dec 18, 2013·Journal of Medicinal Chemistry·Saâdia AsgatayDominique Guianvarc'h
Sep 22, 2016·Clinical Epigenetics·Inês GraçaCarmen Jerónimo
May 18, 2017·The Neuroscientist : a Review Journal Bringing Neurobiology, Neurology and Psychiatry·Gonca Bayraktar, Michael R Kreutz
Dec 16, 2011·Chembiochem : a European Journal of Chemical Biology·Ludovic HalbyPaola B Arimondo
Aug 1, 2013·Biomolecular Concepts·Hari Manev, Svetlana Dzitoyeva
Jul 8, 2020·Journal of Periodontology·Silvana P BarrosPayal Arora
Jan 13, 2015·Expert Review of Clinical Immunology·Xiang LiWeidong Han
Mar 28, 2019·Current Molecular Medicine·Jin Zhou, Jie Sun
Sep 14, 2010·Molecular Cancer Therapeutics·Dirk KuckJose L Medina-Franco

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