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

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 physic...

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Veröffentlicht in:	ACS medicinal chemistry letters 2022-04, Vol.13 (4), p.658-664
Hauptverfasser:	Betschart, Claudia, Faller, Michael, Zink, Florence, Hemmig, René, Blank, Jutta, Vangrevelinghe, Eric, Bourrel, Marjorie, Glatthar, Ralf, Behnke, Dirk, Barker, Kerstin, Heizmann, Andreas, Angst, Daniela, Nimsgern, Pierre, Jacquier, Sébastien, Junt, Tobias, Zipfel, Géraldine, Ruzzante, Giulia, Loetscher, Pius, Limonta, Sarah, Hawtin, Stuart, Andre, Cedric Bernard, Boulay, Thomas, Feifel, Roland, Knoepfel, Thomas
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Schlagworte:	Letter
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creator	Betschart, Claudia Faller, Michael Zink, Florence Hemmig, René Blank, Jutta Vangrevelinghe, Eric Bourrel, Marjorie Glatthar, Ralf Behnke, Dirk Barker, Kerstin Heizmann, Andreas Angst, Daniela Nimsgern, Pierre Jacquier, Sébastien Junt, Tobias Zipfel, Géraldine Ruzzante, Giulia Loetscher, Pius Limonta, Sarah Hawtin, Stuart Andre, Cedric Bernard Boulay, Thomas Feifel, Roland Knoepfel, Thomas
description	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.
doi_str_mv	10.1021/acsmedchemlett.1c00696
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source	ACS Publications; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central
subjects	Letter
title	Structure-Based Optimization of a Fragment-like TLR8 Binding Screening Hit to an In Vivo Efficacious TLR7/8 Antagonist
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