2-Aminopyrimidine Derivatives as New Selective Fibroblast Growth Factor Receptor 4 (FGFR4) Inhibitors

ACS Medicinal Chemistry Letters
Cheng MoKe Ding

Abstract

A series of 2-aminopyrimidine derivatives were designed and synthesized as highly selective FGFR4 inhibitors. One of the most promising compounds 2n tightly bound FGFR4 with a Kd value of 3.3 nM and potently inhibited its enzymatic activity with an IC50 value of 2.6 nM, but completely spared FGFR1/2/3. The compound selectively suppressed proliferation of breast cancer cells harboring dysregulated FGFR4 signaling with an IC50 value of 0.38 μM. Furthermore, 2n exhibited extraordinary target specificity in a Kinome-wide screen against 468 kinases, with S(35) and S(10) selectivity scores of 0.01 and 0.007 at 1.0 μM, respectively.

References

May 28, 1993·International Journal of Cancer. Journal International Du Cancer·S JaakkolaH Nevanlinna
Oct 12, 2004·Trends in Genetics : TIG·Nobuyuki Itoh, David M Ornitz
May 3, 2005·Cytokine & Growth Factor Reviews·V P EswarakumarJ Schlessinger
Dec 29, 2005·Molecular Cancer Research : MCR·Véronique Gelsi-BoyerMax Chaffanet
Jul 14, 2007·The Journal of Biological Chemistry·Benjamin C LinLuc R Desnoyers
Feb 26, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Andreas RoidlAxel Ullrich
Oct 16, 2009·Journal of Medicinal Chemistry·Frank LoveringChristine Humblet
Mar 27, 2010·Chemistry & Biology·Wenjun ZhouNathanael S Gray
Feb 4, 2012·Genes & Development·Matthew J PotthoffDavid J Mangelsdorf
Aug 8, 2013·The American Journal of Pathology·Olav EngebraatenAnne-Lise Børresen-Dale
Aug 16, 2013·Current Pharmaceutical Design·Christine HeinzleBrigitte Marian
Nov 20, 2013·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Abdelbaset BuhmeidaMohammed H Al-Qahtani
Jun 17, 2015·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Mehdi TouatJean-Charles Soria
Sep 2, 2015·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Josep TaberneroJean-Charles Soria
Nov 17, 2015·Nature Reviews. Drug Discovery·Chiara DegirolamoAntonio Moschetta

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Citations

Mar 28, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·You-Lu PanJian-Zhong Chen
Nov 15, 2017·Applied Biochemistry and Biotechnology·Nivya JamesK Ramanathan
Oct 17, 2018·Future Medicinal Chemistry·Nestor Prieto-DominguezYong Teng
Oct 28, 2018·Nature Reviews. Clinical Oncology·Masaru Katoh
May 2, 2019·Chemical Communications : Chem Comm·Zhan ZhouYongheng Chen
Nov 5, 2019·Expert Opinion on Therapeutic Patents·Giuseppe MarsegliaRiccardo Castelli
Mar 25, 2019·Cell Death and Differentiation·S Pauliina TurunenKaisa Lehti
Apr 1, 2020·Chemical Society Reviews·Ayah AbdeldayemPatrick T Gunning
Feb 12, 2021·Journal of Hematology & Oncology·Sitong YueDaichao Wu
Apr 17, 2021·ACS Medicinal Chemistry Letters·Wuqing DengXiaoyun Lu
Jun 12, 2021·Cancer Medicine·Kaili JiangZhang Zhang
Oct 9, 2020·Journal of Medicinal Chemistry·Renata Rezende MirandaChao Zhang
Aug 16, 2019·ACS Medicinal Chemistry Letters·Xiaojing LinChristopher J Squire

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