Optimizing a Weakly Binding Fragment into a Potent
RORγt Inverse Agonist with Efficacy in an in Vivo Inflammation
Model
Posted on 2018-07-10 - 00:00
The
transcription factor RORγt is an attractive drug-target due
to its role in the differentiation of IL-17 producing Th17 cells that
play a critical role in the etiopathology of several autoimmune diseases.
Identification of starting points for RORγt inverse agonists
with good properties has been a challenge. We report the identification
of a fragment hit and its conversion into a potent inverse agonist
through fragment optimization, growing and merging efforts. Further
analysis of the binding mode revealed that inverse agonism was achieved
by an unusual mechanism. In contrast to other reported inverse agonists,
there is no direct interaction or displacement of helix 12 observed
in the crystal structure. Nevertheless, compound 9 proved
to be efficacious in a delayed-type hypersensitivity (DTH) inflammation
model in rats.
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Carcache, David A.; Vulpetti, Anna; Kallen, Joerg; Mattes, Henri; Orain, David; Stringer, Rowan; et al. (2018). Optimizing a Weakly Binding Fragment into a Potent
RORγt Inverse Agonist with Efficacy in an in Vivo Inflammation
Model. ACS Publications. Collection. https://doi.org/10.1021/acs.jmedchem.8b00529
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AUTHORS (17)
DC
David A. Carcache
AV
Anna Vulpetti
JK
Joerg Kallen
HM
Henri Mattes
DO
David Orain
RS
Rowan Stringer
EV
Eric Vangrevelinghe
RW
Romain M. Wolf
KK
Klemens Kaupmann
JO
Johannes Ottl
JD
Janet Dawson
NC
Nigel G. Cooke
KH
Klemens Hoegenauer
AB
Andreas Billich
JW
Juergen Wagner
CG
Christine Guntermann
SH
Samuel Hintermann