Adel Ersek, Myoung Sook Kim, Caterina Suelzu, Isabelle Piec, Aerielle Matsangos, Elmar Nurmemmedov, Emma C Bull, Tabitha Bartlett, Rachel Dunn, James R Dick, Rena Lapidus, Danielle M Copeman, Jonathan C Y Tang, Paul G Crichton, Matthew G Pontifex, William D Fraser, Nicole J Horwood, Antonino Passaniti, Darrell Green
Osteoporosis is a leading cause of age-related morbidity, yet existing antiresorptive and anabolic therapies remain limited by safety concerns, contraindications and poor long-term adherence. CADD522 is a small molecule inhibitor of the RUNX2 transcription factor currently under development for cancer therapy. Here, we investigated whether RUNX2 inhibition could protect against post-menopausal bone loss. In an ovariectomy-induced mouse model, CADD522 (25 mg/kg, three times weekly for eight weeks) enhanced bone formation, preserved trabecular microarchitecture and reduced marrow and peripheral adiposity. Cross-species pharmacokinetic and toxicological studies demonstrated oral bioavailability, favourable short-term tolerability and target engagement despite rapid systemic clearance, while cellular thermal shift assays confirmed direct engagement of RUNX2. Together, these findings identify RUNX2 inhibition as a therapeutic strategy that simultaneously improves skeletal integrity and metabolic homeostasis, supporting further development of CADD522 for osteoporosis and other RUNX2-driven diseases.