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2017 ; 7
(1
): 10806
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English Wikipedia
In search of a small molecule agonist of the relaxin receptor RXFP1 for the
treatment of liver fibrosis
#MMPMID28883402
McBride A
; Hoy AM
; Bamford MJ
; Mossakowska DE
; Ruediger MP
; Griggs J
; Desai S
; Simpson K
; Caballero-Hernandez I
; Iredale JP
; Pell T
; Aucott RL
; Holmes DS
; Webster SP
; Fallowfield JA
Sci Rep
2017[Sep]; 7
(1
): 10806
PMID28883402
show ga
The peptide hormone human relaxin-2 (H2-RLX) has emerged as a potential therapy
for cardiovascular and fibrotic diseases, but its short in vivo half-life is an
obstacle to long-term administration. The discovery of ML290 demonstrated that it
is possible to identify small molecule agonists of the cognate G-protein coupled
receptor for H2-RLX (relaxin family peptide receptor-1 (RXFP1)). In our efforts
to generate a new medicine for liver fibrosis, we sought to identify improved
small molecule functional mimetics of H2-RLX with selective, full agonist or
positive allosteric modulator activity against RXFP1. First, we confirmed
expression of RXFP1 in human diseased liver. We developed a robust cellular cAMP
reporter assay of RXFP1 signaling in HEK293 cells transiently expressing RXFP1. A
high-throughput screen did not identify further specific agonists or positive
allosteric modulators of RXFP1, affirming the low druggability of this receptor.
As an alternative approach, we generated novel ML290 analogues and tested their
activity in the HEK293-RXFP1 cAMP assay and the human hepatic cell line LX-2.
Differences in activity of compounds on cAMP activation compared with changes in
expression of fibrotic markers indicate the need to better understand cell- and
tissue-specific signaling mechanisms and their disease-relevant phenotypes in
order to enable drug discovery.
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