RUNX2 inhibitor CADD522 improves bone microarchitecture and lipid metabolism in post-menopausal bone loss

Ersek, Adel, Kim, Myoung Sook, Suelzu, Caterina, Piec, Isabelle ORCID: https://orcid.org/0000-0002-0648-1330, Matsangos, Aerielle, Nurmemmedov, Elmar, Bull, Emma C. ORCID: https://orcid.org/0009-0008-2250-1179, Bartlett, Tabitha, Dunn, Rachel, Dick, James R., Lapidus, Rena, Copeman, Danielle M., Tang, Jonathan C. Y., Crichton, Paul G. ORCID: https://orcid.org/0000-0003-3786-8359, Pontifex, Matthew G. ORCID: https://orcid.org/0000-0003-2174-2313, Fraser, William D., Horwood, Nicole J. ORCID: https://orcid.org/0000-0002-6344-1677, Passaniti, Antonino and Green, Darrell ORCID: https://orcid.org/0000-0002-0217-3322 (2026) RUNX2 inhibitor CADD522 improves bone microarchitecture and lipid metabolism in post-menopausal bone loss. npj Drug Discovery. ISSN 3005-1452 (In Press)

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Abstract

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, post-menopausal bone loss 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. Cellular thermal shift assays confirmed direct engagement of the RUNX2 protein. Together, these findings identify RUNX2 inhibition as a therapeutic strategy that simultaneously improves skeletal integrity and metabolic homeostasis, supporting further drug development of CADD522 for osteoporosis and other RUNX2-driven diseases.

Item Type:	Article
Additional Information:	Data Availability Statement: All data generated or analysed during this study are included in this published article and its Supplementary Information. Additional datasets and detailed methodological protocols required to support reproducibility are available from the corresponding author upon reasonable request.
Uncontrolled Keywords:	cadd522,runx2,bone loss,bone sarcoma,breast cancer
Faculty \ School:	Faculty of Science > School of Biological Sciences Faculty of Medicine and Health Sciences > Norwich Medical School Faculty of Medicine and Health Sciences > School of Health Sciences
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Groups > Musculoskeletal Medicine Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health Faculty of Medicine and Health Sciences > Research Groups > Cardiovascular and Metabolic Health Faculty of Medicine and Health Sciences > Research Groups > Nutrition and Preventive Medicine
Depositing User:	LivePure Connector
Date Deposited:	17 Aug 2026 13:18
Last Modified:	17 Aug 2026 13:18
URI:	https://ueaeprints.uea.ac.uk/id/eprint/104176
DOI:	issn:3005-1452

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