Identification of small molecules uncoupling the Notch::Jagged interaction through an integrated high-throughput screening

PloS One
Natalia PlatonovaRaffaella Chiaramonte

Abstract

Notch signaling plays an important role in several cellular functions including growth, differentiation, cell fate determination and stemness. Increased Notch activity has been linked to several types of cancers. Activation of Notch signaling is triggered by the interaction of Notch receptors (Notch1-4) with 5 different ligands (Jagged1-2 and Dll1-3-4) expressed on the neighbouring cells. Currently, indirect approaches to inhibit Notch signalling are based on the inhibition of the key step of Notch activation catalyzed by the γ-Secretase and thereby affect several different γ-Secretase substrates; conversely direct strategies get advantage of antibody-based drugs. The evidence that Jagged-mediated Notch activation plays a key role in cancer cell biology and the interplay with the surrounding microenvironment prompted us to develop a strategy to directly inhibit Notch activation by uncoupling its interaction with the Jagged, using an unprecedented approach based on small molecules. We set-up a screening strategy based on: protein::protein docking of crystallographic structures of Notch1 with Jagged1; comparative modelling of the Notch2:Jagged2 complex, based on the Notch1::Jagged1 complex; in silico high-throughput screening dir...Continue Reading

References

Dec 24, 2002·The Journal of Biological Chemistry·Janice M AscanoAnthony J Capobianco
May 4, 2004·American Journal of Human Genetics·Neil V WhittockPeter D Turnpenny
Jun 3, 2004·Nature Reviews. Molecular Cell Biology·Raphael Kopan, Ma Xenia G Ilagan
Jan 24, 2007·Journal of Chemical Information and Modeling·Marwen NaïmEnrico O Purisima
Jul 25, 2007·The Journal of Experimental Medicine·Benjamin J ThompsonIannis Aifantis
Dec 7, 2007·The Journal of Clinical Investigation·Pasquale SansoneMassimiliano Bonafè
Jul 29, 2008·Nature Structural & Molecular Biology·Jemima CordlePenny A Handford
Sep 9, 2008·Human Molecular Genetics·Duncan B SparrowSally L Dunwoodie
Nov 18, 2008·Experimental Hematology·Esther van StralenBert J E G Bast
Nov 22, 2008·Cancer Letters·Zhiwei WangFazlul H Sarkar
Jan 24, 2009·Cellular and Molecular Life Sciences : CMLS·T Borggrefe, F Oswald
May 7, 2009·Cancer Research·Pushpankur GhoshalLionel J Coignet
Jul 14, 2010·Proceedings of the National Academy of Sciences of the United States of America·Pawel K MazurJens T Siveke
Apr 22, 2011·Nature Reviews. Cancer·Prathibha RanganathanAnthony J Capobianco
Jul 12, 2011·Journal of Computer-aided Molecular Design·Ivano EberiniMaria P Abbracchio
Dec 23, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Takahiro MimaeAkihiko Ito
Feb 22, 2012·Blood Cells, Molecules & Diseases·David ChironCatherine Pellat-Deceunynck
Jun 26, 2012·Biochemical and Biophysical Research Communications·Sung Hee LeeKi-Hyuk Shin
Aug 15, 2012·The Journal of Experimental Medicine·Mark J KielKojo S J Elenitoba-Johnson
Nov 1, 2012·Biochemical and Biophysical Research Communications·Dehui XuEls Van Valckenborgh
Sep 4, 2013·Human Mutation·Julie W RuttenSaskia A J Lesnik Oberstein
Apr 20, 2014·Cancer Research·Wei HuAnil K Sood
Sep 27, 2014·Oncotarget·Michela ColomboRaffaella Chiaramonte
Jun 29, 2015·Chaos·Igal Berenstein
Aug 27, 2015·Oncotarget·Michela ColomboRaffaella Chiaramonte
Jan 2, 2016·Clinical Chemistry·Natalia Bednarz-KnollKlaus Pantel
May 10, 2016·Scientific Reports·Cong WangYufeng Cheng
Jun 19, 2016·The American Journal of Pathology·Kazunori KawaguchiShuichi Kaneko

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Citations

Sep 11, 2018·Frontiers in Chemistry·Luca PalazzoloIvano Eberini
Aug 30, 2018·Frontiers in Immunology·Michela ColomboNatalia Platonova
Sep 17, 2020·Cancers·Maria Teresa PalanoRaffaella Chiaramonte
Dec 10, 2020·Nature Reviews. Drug Discovery·Samarpan MajumderLucio Miele
Dec 31, 2020·International Journal of Molecular Sciences·Marco MarchisioPaola Lanuti

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Methods Mentioned

BETA
transfection
Assay

Software Mentioned

OPLS
MOE
Molecular Operating Environment ( MOE )
MOE ‘ Database Minimize
Triangle matcher
MOE ‘ Database Wash
GBVI
MOE Protein contact
MOE ‘ Dock ’
MOE contact

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