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Last update 23 Jan 2025

RXFP2 x RXFP1

Last update 23 Jan 2025

Basic Info

Related Targets

RXFP2RXFP1

Drugs associated with RXFP2 x RXFP1

CGEN-25010

Target

RXFP1 x RXFP2

Mechanism

RXFP1 agonists [+1]

Active Org.-

Originator Org.

Compugen Ltd.

Active Indication-

Inactive Indication

Fibrosis

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

BMS-986259

Target

RXFP1 x RXFP2

Mechanism

RXFP1 agonists [+2]

Active Org.-

Originator Org.

Bristol Myers Squibb Co.

Active Indication-

Inactive Indication

Acute decompensated heart failure

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with RXFP2 x RXFP1

NCT04318093

/ CompletedPhase 2

A Randomized, Double-Blinded, Placebo-Controlled, Study to Evaluate the Safety and Tolerability of BMS-986259 in Stabilized Patients Hospitalized for Acute Decompensated Heart Failure

The purpose of the study is to assess the safety of BMS-986259 in stable participants hospitalized for acute decompensated heart failure.

Start Date06 Nov 2020

Sponsor / Collaborator

Bristol Myers Squibb Co.

NCT04237831

/ CompletedPhase 1

A Phase 1, Open-Label, Multiple-Dose Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of BMS-986259 in Participants With Varying Degrees of Renal Function

A study to evaluate the drug effect, safety, and tolerability of BMS-986259 in participants with different levels of kidney function

Start Date26 Feb 2020

Sponsor / Collaborator

Bristol Myers Squibb Co.

NL-OMON49614

/ CompletedNot ApplicableIIT

A randomized, double-blinded, placebo-controlled, single and multiple ascending dose study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of BMS-986259 in healthy participants - BMS-986259 FIH SAD MAD study

Start Date18 Jun 2019

Sponsor / Collaborator-

100 Clinical Results associated with RXFP2 x RXFP1

100 Translational Medicine associated with RXFP2 x RXFP1

0 Patents (Medical) associated with RXFP2 x RXFP1

134

Literatures (Medical) associated with RXFP2 x RXFP1

01 May 2022·The FASEB Journal

RXFP2 Small Molecule Agonists: Potential Therapeutics for Osteoporosis

Article

Author: Myhr, Courtney ; Barnaeva, Elena ; Esteban‐Lopez, Maria ; Marugan, Juan ; Southall, Noel ; Hu, Xin ; Wilson, Kenneth ; Ferrer, Marc ; Kaftanovskaya, Elena ; Agoulnik, Irina ; Agoulnik, Alexander ; Ye, Wenjuan ; Kim, David ; Henderson, Mark ; Morello, Roy

Osteoporosis is a chronic bone disease characterized by decreased bone mass and increased risk of developing fractures, predominantly observed in the elderly. Osteoporosis affects approximately 10 million people in the US, and the number is expected to increase exponentially as the elderly population continues to grow. The pathophysiological cause of the disease is a decrease in the activity of the bone‐forming cells (osteoblasts) that alters bone remodeling in favor of bone resorption, leading to a decrease in bone mass. Recent studies identified the G protein‐coupled receptor (GPCR) for insulin‐like 3 peptide (INSL3), relaxin family peptide receptor 2 (RXFP2), as an attractive target for the treatment of osteoporosis. The goal of this study is to develop small molecule agonists of RXFP2, expressed in osteoblast cells, to promote bone growth and counteract the deleterious effects of osteoporosis. Currently, the most effective available treatment for osteoporosis is an expensive hormone therapy that requires daily injections. We aim to create drugs that are stable and can be delivered orally. Several low molecular weight compounds were identified as agonists of the RXFP2 receptor using a high‐throughput screen of the NCATS small molecule library. The screening assay measured cAMP response in RXFP2‐transfected HEK293T cells. An extensive structure‐activity relationship campaign resulted in highly potent and efficient full RXFP2 agonists. The selectivity and specificity of the compounds for human and mouse RXFP2 was shown using orthogonal cAMP assays, counter‐screening against the related relaxin receptor RXFP1, and a GPCRome screen using the PRESTO‐Tango assay. The drug candidates were further tested in primary human osteoblasts to demonstrate that they promote mineralization by measuring hydroxyapatite deposition in the cell matrix. We showed that the compounds had low cytotoxicity in various cell types. Using a series of RXFP2/RXFP1 chimeric receptors, we established that the compounds are allosteric agonists of the RXFP2 receptor and identified the GPCR transmembrane domains as the specific region for compound interaction. The RXFP2 agonist with the highest activity in vitro was selected for pharmacokinetics (PK) profiling in mice, showing optimal oral bioavailability and bone exposure. An efficacy study using 2‐month‐old WT female mice treated orally with 10 mg/kg of compound 3 times a week for 8 weeks showed a significant increase of the vertebral trabecular number and thickness by micro‐CT analysis compared to vehicle treated controls. We expect that the further characterization of these compounds may lead to the development of a new class of cost‐effective drugs for the treatment of osteoporosis and other diseases associated with bone loss.

01 Oct 2021·Journal of Molecular BiologyQ2 · BIOLOGY

Structural Insights into the Unique Modes of Relaxin-Binding and Tethered-Agonist Mediated Activation of RXFP1 and RXFP2

Q2 · BIOLOGY

Article

Author: Emma J. Petrie ; Riley D. Metcalfe ; Mohammad Hossein Tanipour ; Ashish Sethi ; Fei Yan ; Chris Draper-Joyce ; Michael D.W. Griffin ; Tim Ryan ; Yogesh Khandokar ; Paul R. Gooley ; Shoni Bruell ; Yee-Foong Mok ; Ross A.D. Bathgate ; Mohammad Akhter Hossain ; Daniel J. Scott

Our poor understanding of the mechanism by which the peptide-hormone H2 relaxin activates its G protein coupled receptor, RXFP1 and the related receptor RXFP2, has hindered progress in its therapeutic development. Both receptors possess large ectodomains, which bind H2 relaxin, and contain an N-terminal LDLa module that is essential for receptor signaling and postulated to be a tethered agonist. Here, we show that a conserved motif (GDxxGWxxxF), C-terminal to the LDLa module, is critical for receptor activity. Importantly, this motif adopts different structures in RXFP1 and RXFP2, suggesting distinct activation mechanisms. For RXFP1, the motif is flexible, weakly associates with the LDLa module, and requires H2 relaxin binding to stabilize an active conformation. Conversely, the GDxxGWxxxF motif in RXFP2 is more closely associated with the LDLa module, forming an essential binding interface for H2 relaxin. These differences in the activation mechanism will aid drug development targeting these receptors.

01 Aug 2021·BiochimieQ3 · BIOLOGY

Relaxin in hepatic fibrosis: What is known and where to head?

Q3 · BIOLOGY

Review

Author: Ezhilarasan, Devaraj

Relaxin (RLX) is a heterodimeric, polypeptide hormone that has natural anti-fibrotic activity in many organs. During the chronic liver injury, hepatic stellate cells (HSCs) are phenotypically transformed into myofibroblasts. This process is known as activation of HSCs. Activated HSCs play a central role in hepatic fibrosis. Quiescent HSCs were shown to express low levels of RLX receptors such as RXFP1 and RXFP2. Upon chronic liver injury, HSCs are activated and express high levels of the RLX receptors. ML290, an agonist of RXFP1 has been reported to have antifibrotic effect in vitro as well as in vivo. Serelaxin, a recombinant human RLX-2 treatment has reduced hepatic fibrosis and portal hypertension in experimental models due to its vasodilation properties by inducing intrahepatic nitric oxide level. Serelaxin has also produced a neutral effect when studied against human cirrhosis-related portal hypertension in clinical trials. RLX is a potent collagen synthesis inhibitor and it has extracellular matrix (ECM) remodeling properties by promoting matrix metalloproteinases and downregulating expression of metalloproteinases inhibitors. Available reports suggest that RLX could induce ECM remodeling and suppress the profibrogenic transforming growth factor-β signaling and thereby regress hepatic fibrosis. Though RLX has natural antifibrotic activity, its antifibrotic molecular mechanisms especially in hepatic fibrosis condition are not reported. This review exclusively focuses antifibrotic effect of RLX on hepatic fibrosis.

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