Structure-Guided Discovery of Potent and Selective CLK2 Inhibitors for the Treatment of Knee Osteoarthritis

Osteoarthritis is the most common joint disorder. However, there are no disease-modifying drugs approved for OA treatment. CDC2-like kinase 2 (CLK2) could modulate Wnt signaling via alternative splicing of Wnt target genes and further affect bone differentiation, chondrocyte function, and inflammation, making CLK2 an attractive target for OA therapy. In this study, we designed and synthesized a series of highly potent CLK2 inhibitors based on Indazole 1. Among them, compound LQ23 showed more elevated inhibitory activity against CLK2 than the lead compound (IC50, 1.4 nM) with high CLK2/CLK3 selectivity (>70-fold). Furthermore, LQ23 showed outstanding antiosteoarthritis effects in vitro and in vivo, with the roles specific in decreased inflammatory cytokines, downregulated cartilage degradative enzymes, and increased joint cartilage via suppressing CLK2/Wnt signaling pathway. Overall, these data support LQ23 as a potential candidate for intra-articular knee OA therapy, leveraging its unique mechanism of action for targeted treatment.