In search of a small molecule agonist of the relaxin receptor RXFP1 for the treatment of liver fibrosis

McBride, Andrew; Hoy, Anna M.; Bamford, Mark J.; Mossakowska, Danuta E.; Ruediger, Martin P.; Griggs, Jeremy; Desai, Sapna; Simpson, Kate; Caballero-Hernandez, Ivan; Iredale, John P.; Pell, Theresa J.; Aucott, Rebecca L.; Holmes, Duncan S.; Webster, Scott P.; Fallowfield, Jonathan

doi:10.1038/s41598-017-10521-9

Cited by 22 publications

(18 citation statements)

References 45 publications

(60 reference statements)

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“…[117] The small molecule, ML290, has been described as an RXFP1 agonist, resulting in increased cAMP levels and reduced collagen I gene expression in chronic liver disease. [118] In addition, ML290 has been shown to have similar signaling responses as RLX (e.g. increased cAMP through certain G-coupled proteins, p38MAPK, MMP-2, pSMAD2 and cGMP), while they differed in active p-ERK1/2 levels, though, interestingly, priming with ML290 enhanced…”

Section: Relaxin Mimeticsmentioning

confidence: 99%

“…ML290 appears to be an RXPF1 agonist in humans, monkey's and pigs, and an antagonist in mice, suggesting species bias in ML290 signaling. [118,119,120] However, studies with mouse RXFP1 replaced with humanized RXFP1 have shown that animal models can be developed to study the effects of ML290 in smaller rodents. [121] In contrast to RLX, ML290 has been shown to have a half-life in the heart and plasma of ~8 hours, opening the possibility of longer lasting effects with less treatment time.…”

Section: Relaxin Mimeticsmentioning

confidence: 99%

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Cardioprotective actions of relaxin

Martin

Romero

Salama

2019

Molecular and Cellular Endocrinology

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Relaxin, a hormone of pregnancy, has shown broad cardioprotective effects including anti-fibrotic (reversed excess TGFβ signaling), anti-arrhythmic (Nav1.5 and INa upregulation and Cx43 phosphorylation and trafficking to intercalated disks) and anti-inflammatory properties (reduced IL-1β and IL-6). While relaxin's anti-fibrotic effects are thought to occur through the SMAD2/3/TGFβ pathway, there is a general lack of understanding of relaxin's mode of action to increase sodium current and alter connexin43 localization to suppress arrhythmias. Based on a rat model of aging, we tested the hypothesis that relaxin acts through activation of Wnt/βcatenin signaling to mediate its effects on Nav1.5 and Cx43 and to regulate collagen expression. We show for the first time that relaxin activates canonical Wnt signaling (increased nuclear βcatenin) to increase Nav1.5 in isolated cardiomyocytes. Block of canonical Wnt signaling (via Dikkopf-1) abrogated relaxin's effect on both Nav1.5 in cardiomyocytes and suppression of excess collagen from fibroblasts. Further, we show that relaxin significantly suppressed expression of Dikkopf-1 in isolated cardiomyocytes and whole LV tissue. In addition, show that relaxin suppressed the age-associated genetic upregulation in inflammatory markers in a sexdependent manner. Finally, we tested the hypothesis that relaxin would be an effective therapy in a rat model of pulmonary arterial hypertension and show that it reduced occlusion of small pulmonary arteries, myocardial and lung fibrosis and reversed the cardiac phenotype of ventricular arrhythmia or arrest. These results suggest that relaxin signals through multiple

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Section: Relaxin Mimeticsmentioning

confidence: 99%

Section: Relaxin Mimeticsmentioning

confidence: 99%

Cardioprotective actions of relaxin

Martin

Romero

Salama

2019

Molecular and Cellular Endocrinology

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“…Similar results have been recently reported by another group in the HSC LX-2 cell line using ML-290. 29…”

Section: Resultsmentioning

confidence: 99%

Optimization of the first small-molecule relaxin/insulin-like family peptide receptor (RXFP1) agonists: Activation results in an antifibrotic gene expression profile

Wilson

Xiao

Chen

et al. 2018

European Journal of Medicinal Chemistry

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A dose responsive quantitative high throughput screen (qHTS) of >350,000 compounds against a human relaxin/insulin-like family peptide receptor (RXFP1) transfected HEK293 cell line identified 2-acetamido-N-phenylbenzamides 1 and 3 with modest agonist activity. An extensive structure-activity study has been undertaken to optimize the potency, efficacy, and physical properties of the series, resulting in the identification of compound 65 (ML-290), which has excellent in vivo PK properties with high levels of systemic exposure. This series, exemplified by 65, has produced first-in-class small-molecule agonists of RXFP1 and is a potent activator of anti-fibrotic genes.

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“…Previously, we demonstrated that despite lower activity in the cAMP assay, ML290 showed higher efficacy in other relaxin‐dependent cellular and gene activation tests than several other compounds in this series (20). Here, we tested 5 different compounds to select the agonist most effective at targeting expression of several genes involved in remodeling of ECM in primary HSCs (22, 30). ML290 consistently suppressed COL1A1 and TGFB1 expression and up‐regulated the previously established relaxin target PPARGC1A (38).…”

Section: Discussionmentioning

confidence: 99%

Therapeutic effects of a small molecule agonist of the relaxin receptor ML290 in liver fibrosis

Kaftanovskaya

Soula

et al. 2019

The FASEB Journal

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Fibrosis is an underlying cause of cirrhosis and hepatic failure resulting in end stage liver disease with limited pharmacological options. The beneficial effects of relaxin peptide treatment were demonstrated in clinically relevant animal models of liver fibrosis. However, the use of relaxin is problematic because of a short half‐life. The aim of this study was to test the therapeutic effects of recently identified small molecule agonists of the human relaxin receptor, relaxin family peptide receptor 1 (RXFP1). The lead compound of this series, ML290, was selected based on its effects on the expression of fibrosis‐related genes in primary human stellate cells. RNA sequencing analysis of TGF‐β1–activated LX‐2 cells showed that ML290 treatment primarily affected extracellular matrix remodeling and cytokine signaling, with expression profiles indicating an antifibrotic effect of ML290. ML290 treatment in human liver organoids with LPS‐induced fibrotic phenotype resulted in a significant reduction of type I collagen. The pharmacokinetics of ML290 in mice demonstrated its high stability in vivo, as evidenced by the sustained concentrations of compound in the liver. In mice expressing human RXFP1 gene treated with carbon tetrachloride, ML290 significantly reduced collagen content, α‐smooth muscle actin expression, and cell proliferation around portal ducts. In conclusion, ML290 demonstrated antifibrotic effects in liver fibrosis.—Kaftanovskaya, E. M., Ng, H. H., Soula, M., Rivas, B., Myhr, C., Ho, B. A., Cervantes, B. A., Shupe, T. D., Devarasetty, M., Hu, X., Xu, X., Patnaik, S., Wilson, K. J., Barnaeva, E., Ferrer, M., Southall, N. T., Marugan, J. J., Bishop, C. E., Agoulnik, I. U., Agoulnik, A. I. Therapeutic effects of a small molecule agonist of the relaxin receptor ML290 in liver fibrosis. FASEB J. 33, 12435–12446 (2019). http://www.fasebj.org

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In search of a small molecule agonist of the relaxin receptor RXFP1 for the treatment of liver fibrosis

Cited by 22 publications

References 45 publications

Cardioprotective actions of relaxin

Cardioprotective actions of relaxin

Optimization of the first small-molecule relaxin/insulin-like family peptide receptor (RXFP1) agonists: Activation results in an antifibrotic gene expression profile

Therapeutic effects of a small molecule agonist of the relaxin receptor ML290 in liver fibrosis

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