Identification of a RANKL/TNF-α Dual-Inhibitor as a Potential Disease-Modifying Agent for the Treatment of Knee Osteoarthritis

Osteoarthritis (OA) is a multifactorial degenerative disease involved subchondral bone remodeling, cartilage destruction and synovium inflammation. While receptor activator of nuclear factor-κB ligand (RANKL), a tumor necrosis factor (TNF) superfamily protein, is the critical regulator in bone metabolism associated with subchondral bone resorption, TNF-α is also an important inflammatory factor involved in the OA inflammation and cartilage destruction. Based on previous compound Y1599, we identified a novel tetrahydro-β-carboline derivative Y2641 with both RANKL and TNF-α inhibition in this study. Y2641 exhibited potent RANKL-induced osteoclastogenic inhibition (IC50 = 109.1 nM), and had anti-inflammatory and cartilage destruction inhibiting effects at 10 μM with low cytotoxicity. SPR assays demonstrated the binding affinity of Y2641 to RANKL (Kd = 3.984 μM) and TNF-α (Kd = 18.59 μM). In vivo assay further revealed the disease-modifying effects of Y2641 in OA rats, establishing Y2641 as a promising lead compound for the development of disease-modifying osteoarthritis drugs.