Literature DB >> 35450354

Structure-Based Optimization of a Fragment-like TLR8 Binding Screening Hit to an In Vivo Efficacious TLR7/8 Antagonist.

Claudia Betschart1, Michael Faller2, Florence Zink2, René Hemmig2, Jutta Blank2, Eric Vangrevelinghe1, Marjorie Bourrel1, Ralf Glatthar1, Dirk Behnke1, Kerstin Barker1, Andreas Heizmann1, Daniela Angst1, Pierre Nimsgern1, Sébastien Jacquier1, Tobias Junt3, Géraldine Zipfel3, Giulia Ruzzante3, Pius Loetscher3, Sarah Limonta3, Stuart Hawtin3, Cedric Bernard Andre3, Thomas Boulay3, Roland Feifel4, Thomas Knoepfel1.   

Abstract

Inappropriate activation of TLR7 and TLR8 is linked to several autoimmune diseases, such as lupus erythematosus. Here we report on the efficient structure-based optimization of the inhibition of TLR8, starting from a co-crystal structure of a small screening hit. Further optimization of the physicochemical properties for cellular potency and expansion of the structure-activity relationship for dual potency finally resulted in a highly potent TLR7/8 antagonist with demonstrated in vivo efficacy after oral dosing.
© 2022 American Chemical Society.

Entities:  

Year:  2022        PMID： 35450354      PMCID： PMC9014506          DOI： 10.1021/acsmedchemlett.1c00696

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.632


  24 in total

1.  Volume of Distribution in Drug Design.

Authors:  Dennis A Smith; Kevin Beaumont; Tristan S Maurer; Li Di
Journal:  J Med Chem       Date:  2015-04-01       Impact factor: 7.446

2.  Structural Evolution and Translational Potential for Agonists and Antagonists of Endosomal Toll-like Receptors.

Authors:  Arindam Talukdar; Dipyaman Ganguly; Swarnali Roy; Nirmal Das; Dipika Sarkar
Journal:  J Med Chem       Date:  2021-06-09       Impact factor: 7.446

3.  Discovery of M5049: A Novel Selective Toll-Like Receptor 7/8 Inhibitor for Treatment of Autoimmunity.

Authors:  Jaromir Vlach; Andrew T Bender; Melinda Przetak; Albertina Pereira; Aditee Deshpande; Theresa L Johnson; Sonja Reissig; Evgeni Tzvetkov; Djordje Musil; Noune Tahmassian Morse; Philipp Haselmayer; Simone C Zimmerli; Shinji L Okitsu; Robert L Walsky; Brian Sherer
Journal:  J Pharmacol Exp Ther       Date:  2020-12-16       Impact factor: 4.030

4.  Discovery of potent, orally bioavailable in vivo efficacious antagonists of the TLR7/8 pathway.

Authors:  Phil B Alper; Jonathan Deane; Claudia Betschart; David Buffet; Géraldine Collignon Zipfel; Perry Gordon; Janice Hampton; Stuart Hawtin; Maureen Ibanez; Tao Jiang; Tobias Junt; Thomas Knoepfel; Bo Liu; Jillian Maginnis; Una McKeever; Pierre-Yves Michellys; Daniel Mutnick; Bishnu Nayak; Satoru Niwa; Wendy Richmond; James S Rush; Peter Syka; Yi Zhang; Xuefeng Zhu
Journal:  Bioorg Med Chem Lett       Date:  2020-06-24       Impact factor: 2.823

5.  Control of toll-like receptor 7 expression is essential to restrict autoimmunity and dendritic cell proliferation.

Authors:  Jonathan A Deane; Prapaporn Pisitkun; Rebecca S Barrett; Lionel Feigenbaum; Terrence Town; Jerrold M Ward; Richard A Flavell; Silvia Bolland
Journal:  Immunity       Date:  2007-11-08       Impact factor: 31.745

6.  Target-Based Identification and Optimization of 5-Indazol-5-yl Pyridones as Toll-like Receptor 7 and 8 Antagonists Using a Biochemical TLR8 Antagonist Competition Assay.

Authors:  Thomas Knoepfel; Pierre Nimsgern; Sébastien Jacquier; Marjorie Bourrel; Eric Vangrevelinghe; Ralf Glatthar; Dirk Behnke; Phil B Alper; Pierre-Yves Michellys; Jonathan Deane; Tobias Junt; Géraldine Zipfel; Sarah Limonta; Stuart Hawtin; Cedric Andre; Thomas Boulay; Pius Loetscher; Michael Faller; Jutta Blank; Roland Feifel; Claudia Betschart
Journal:  J Med Chem       Date:  2020-07-30       Impact factor: 7.446

7.  Cryo-EM structures of Toll-like receptors in complex with UNC93B1.

Authors:  Hanako Ishida; Jinta Asami; Zhikuan Zhang; Tomohiro Nishizawa; Hideki Shigematsu; Umeharu Ohto; Toshiyuki Shimizu
Journal:  Nat Struct Mol Biol       Date:  2021-01-11       Impact factor: 15.369

8.  Recent trends in the development of Toll-like receptor 7/8-targeting therapeutics.

Authors:  Xuan Huang; Xiaoyong Zhang; Mengji Lu
Journal:  Expert Opin Drug Discov       Date:  2021-03-15       Impact factor: 6.098

9.  RNA recognition by human TLR8 can lead to autoimmune inflammation.

Authors:  Cristiana Guiducci; Mei Gong; Alma-Martina Cepika; Zhaohui Xu; Claudio Tripodo; Lynda Bennett; Chad Crain; Pierre Quartier; John J Cush; Virginia Pascual; Robert L Coffman; Franck J Barrat
Journal:  J Exp Med       Date:  2013-11-25       Impact factor: 14.307

Review 10.  Agonist and antagonist ligands of toll-like receptors 7 and 8: Ingenious tools for therapeutic purposes.

Authors:  Cindy Patinote; Nour Bou Karroum; Georges Moarbess; Natalina Cirnat; Issam Kassab; Pierre-Antoine Bonnet; Carine Deleuze-Masquéfa
Journal:  Eur J Med Chem       Date:  2020-03-17       Impact factor: 6.514
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