ML-290 is the first potent, selective, and metabolically stable small-molecule biased allosteric agonist of the relaxin receptor RXFP1, with an EC50 value of 94nM[1,2]. ML-290 is metabolically stable and commonly used in research on fibrosis and inflammation-related diseases, such as chronic kidney disease and liver fibrosis[2,3].
In vitro, treatment of human cardiac fibroblasts (HCF) with ML-290 (1μM) for 72h promoted MMP-2 expression and inhibited TGF-β1-induced phosphorylation of Smad2 and Smad3[1]. In human hepatic stellate cells (HSCs), ML-290 (5μM) treatment for 72h reduced COL1A1 gene expression while increasing the expression of MMP1 and PPARGC1A[4]. In LX-2 cells, a 24h treatment with ML-290 (100μM) downregulated RXFP1 mRNA expression by 9.8 ± 6.4-fold[5]. In HEK293T cells transiently transfected with two rabbit RXFP1 receptor variants (R1-RXFP1 and R2-RXFP2), ML-290 (5μM) treatment for 60min effectively stimulated cAMP production, though with lower potency compared to its effect on human RXFP1[6].
In vivo, a single intraperitoneal injection of ML-290 (37mg/kg) concurrently with CCl4 in humanized hRXFP1/hRXFP1 mice significantly suppressed the upregulation of pro-fibrotic genes (Acta2, Col1a1, and Tgfb1) in the liver at 20h post-treatment[4]. Intravenous administration of ML-290 (100μg/25 g body weight) in humanized hRXFP1/hRXFP1 female mice significantly increased heart rate within 26-40min after injection[7]. In a unilateral ureteral obstruction (UUO) model, intraperitoneal injection of ML-290 (30mg/kg; once daily) for 5 days in humanized hRXFP1/hRXFP1 mice significantly reduced renal apoptosis and inhibited Erk1/2 activity[8].
References:
[1] KOCAN M, SARWAR M, ANG S Y, et al. ML290 is a biased allosteric agonist at the relaxin receptor RXFP1[J]. Scientific Reports, 2017, 7: 2968.
[2] XIAO J, CHEN C Z, HUANG Z, et al. Discovery, optimization, and biological activity of the first potent and selective small-molecule agonist series of human relaxin receptor 1 (RXFP1)[EB/OL]. Probe Reports from the NIH Molecular Libraries Program, 2013-05-08.
[3] NG H H, MEDINA D, AGOULNIK A I, et al. A Novel Human Relaxin Receptor Agonist, ML290, Attenuates Atherosclerosis-and Chronic Kidney Disease-Induced Vascular Calcification in Mice[J]. Circulation, 2020, 142(Suppl_3): A17021-A17021.
[4] KAFTANOVSKAYA E M, NG H H, SOULA M, et al. Therapeutic effects of a small molecule agonist of the relaxin receptor ML290 in liver fibrosis[J]. The FASEB Journal, 2019, 33(11): 12435.
[5] MCBRIDE A, HOY A M, BAMFORD M J, et al. In search of a small molecule agonist of the relaxin receptor RXFP1 for the treatment of liver fibrosis[J]. Scientific Reports, 2017, 7: 10806.
[6] HUANG Z, MYHR C, BATHGATE R A D, et al. Activation of relaxin family receptor 1 from different mammalian species by relaxin peptide and small-molecule agonist ML290[J]. Frontiers in Endocrinology, 2015, 6: 128.
[7] KAFTANOVSKAYA E M, SOULA M, MYHR C, et al. Human relaxin receptor is fully functional in humanized mice and is activated by small molecule agonist ML290[J]. Journal of the Endocrine Society, 2017, 1(6): 712-725.
[8] NG H H, SOULA M, RIVAS B, et al. Anti-apoptotic and matrix remodeling actions of a small molecule agonist of the human relaxin receptor, ML290 in mice with unilateral ureteral obstruction[J]. Frontiers in Physiology, 2021, 12: 650769.
ML-290是首个针对松弛素受体RXFP1，具有高效选择性且稳定的小分子偏向变构激动剂，EC50值为94nM[1,2]。ML-290代谢稳定，常用于纤维化和炎症相关疾病（如慢性肾病和肝纤维化）的研究[2,3]。
在体外，ML-290（1μM）处理人心脏成纤维HCF细胞72h，促进了MMP-2的表达并抑制了由TGF-β1诱导的Smad2和Smad3磷酸化[1]。ML-290（5μM）处理人肝星状HSCs细胞72h，降低了COL1A1基因表达的同时增加了MMP1和PPARGC1A的基因表达[4]。ML-290（100μM）处理LX-2细胞24h，使RXFP1的mRNA表达水平降低了9.8 ± 6.4倍[5]。ML-290（5μM）处理瞬时转染了两种兔RXFP1受体（R1-RXFP1和R2-RXFP2）的HEK293T细胞60min，可有效刺激并增加cAMP的产生，但效能低于人RXFP1受体的作用[6]。
在体内，ML-290（37mg/kg）通过腹腔单次注射与CCl4同时处理人源化hRXFP1/hRXFP1小鼠，20h后显著抑制了肝脏中促纤维化基因Acta2、Col1a1和Tgfb1的表达升高[4]。ML-290（100μg/25g体重）通过静脉注射处理人源化hRXFP1/hRXFP1雌鼠，在注射后26-40min内显著增加了心率[7]。ML-290（30mg/kg; once daily）通过腹膜注射治疗经单侧输尿管梗阻（UUO）手术的人源化hRXFP1/hRXFP1小鼠，持续5天后显著减少了UUO肾脏中细胞的凋亡，并抑制了Erk1/2的活性[8]。