From Lab to Clinic: How RXFP1-Humanized Mice are Paving the Way for Next-Generation Cardiovascular Therapeutics

The relaxin receptor RXFP-1 plays a pivotal role in cardiovascular health. Widely expressed in the heart, kidneys, and blood vessels, RXFP-1 is activated by relaxin, an endogenous heterodimeric insulin-like peptide. Beyond regulating cardiovascular functions such as renal blood flow, relaxin exerts anti-fibrotic, anti-inflammatory, and angiogenic effects, positioning the RXFP-1 pathway as a promising therapeutic target for conditions including heart failure and liver fibrosis.

From Recombinant Peptides to Small-Molecule Innovation

Early clinical trials with ecombinant relaxin analogs (e.g., Serelaxin) underscored the therapeutic potential of RXFP-1 modulation. However, these peptide-based drugs were limited by their short half-life and requirement for intravenous administration, reducing patient convenience and therapeutic utility. 

This challenge accelerated efforts to identify small-molecule RXFP-1 agonists (e.g., ML-290). A high-throughput screening campaign by the US NIH tested over 350,000 compounds and identified ML-290 as a first-in-class small-molecule agonist. Building on this discovery, AstraZeneca invested early a decade optimizing the compound, culminating in AZD5462. This molecule retains relaxin’s activity, stimulating RXFP-1 to enhance endothelium-mediated vasodilation, while delivering cardioprotective and anti-fibrotic benefits. 

RXFP-1 Humanized Mice: A Translational Bridge

To evaluate the pharmacological activity of these compounds, GemPharmatech has developed a RXFP1-humanized mouse strain (B6-hRXFP1 | Strain NO. T065987). This model enables direct in vivo testing of RXFP-1 targeted therapeutics, ensuring results are highly translatable to human biology. 

In pharmacodynamic studies:

• ML-290 treatment in anesthetized B6-hRXFP1 mice induced a gradual increase in heart rate.

• AZD5462 analogs promoted a progressive rise in renal artery blood flow, demonstrating vascular and renal responses consistent with relaxin biology. 

Figure 1 Increase in heart rate in B6-hRXFP1 mice following ML-290 administration

Note: Data are presented as Mean±SEM; n=3-5.

Figure 2 Renal artery dilation and increased renal blood flow in B6-hRXFP1 mice following administration of AZD5462 analogs

Note: Data are presented as Mean±SEM; n=2. A. Transverse color Doppler image of renal blood flow (red: flow toward transducer). The vertical yellow line indicates the sampling region for spectral analysis. B. Corresponding spectral Doppler waveform. C. The changes in renal artery internal diameter after drug administration. D. Changes in renal blood flow (RBF) after drug administration. The calculation formula is: RBF (μL/min) = Luminal Cross-Sectional Area (mm²) × Blood Flow Velocity (mm/s) × 60 s.