SR3335 is a highly potent and selective inverse agonist of retinoic acid receptor-related orphan receptor alpha (RORα), with a Ki value of 220nM[1]. RORα is a member of the nuclear receptor superfamily that functions as a transcription factor regulating lipid metabolism, circadian rhythm, immune responses, and cellular differentiation[2]. SR3335 is commonly used in studies on obesity treatment, as well as metabolic disorders, autoimmune diseases, and inflammatory conditions[3,4].
In vitro, SR3335 (20μM) pretreatment for 4h followed by high glucose (33.3mM) stimulation of cardiac fibroblasts for 48h increased the number of 5-ethynyl-2’-deoxyuridine (EdU)-positive cells and elevated the protein expression level of proliferating cell nuclear antigen (PCNA)[5]. SR3335 (2μM) treatment of bone marrow mesenchymal stem cells (BMSCs) for 14 days significantly promoted adipogenic differentiation of BMSCs[6]. SR3335 (1μM) pretreatment of human nucleus pulposus cells for 2h followed by TNF-α (10ng/mL) treatment significantly restored the TNF-α-induced downregulation of Collagen type II (COL2A1) and Aggrecan (ACAN) mRNA expression levels[7].
In vivo, SR3335 (15mg/kg; twice daily) administered via intraperitoneal injection to C57BL/6J mice with laser-induced choroidal neovascularization (CNV) for 8 days (from day 0 to day 7 post-laser) significantly increased CNV lesion area and the proportion of fundus vascular leakage[8].
References:
[1] KUMAR N, KOJETIN D J, SOLT L A, et al. Identification of SR3335 (ML-176): a synthetic RORα selective inverse agonist[J]. ACS Chemical Biology, 2011, 6(3): 218-222.
[2] JETTEN A M. Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism[J]. Nuclear Receptor Signaling, 2009, 7(1): nrs.07003.
[3] KAMENECKA T M, LYDA B, CHANG M R, et al. Synthetic modulators of the retinoic acid receptor-related orphan receptors[J]. MedChemComm, 2013, 4(5): 764-776.
[4] AUCLAIR M, ROBLOT N, CAPEL E, et al. Pharmacological modulation of RORα controls fat browning, adaptive thermogenesis, and body weight in mice[J]. American Journal of Physiology-Endocrinology and Metabolism, 2021, 320(2): E219-E233.
[5] SAN W, ZHOU Q, SHEN D, et al. Roles of retinoic acid-related orphan receptor α in high glucose-induced cardiac fibroblasts proliferation[J]. Frontiers in Pharmacology, 2025, 16: 1539690.
[6] HE L, CHEN Z, HE T, et al. Retinoic acid-related orphan nuclear receptor alpha inhibits adipogenic differentiation of bone marrow mesenchymal stem cells via activating WNT/β-catenin signaling pathway[J]. European Journal of Medical Research, 2025, 30(1): 1073.
[7] LIANG T, QIU J, LI S, et al. Inverse Agonist of Retinoid‐Related Orphan Receptor‐Alpha Prevents Apoptosis and Degeneration in Nucleus Pulposus Cells via Upregulation of YAP[J]. Mediators of Inflammation, 2021, 2021(1): 9954909.
[8] LIU C H, YEMANYI F, BORA K, et al. Genetic deficiency and pharmacological modulation of RORα regulate laser-induced choroidal neovascularization[J]. Aging (Albany NY), 2023, 15(1): 37.