Researchers identify a PRC1.1 inhibitor for treating bone deterioration disorders

A recent collaborative study by the Guangzhou Institutes of Biomedicine and Health (GIBH) of the Chinese Academy of Sciences (CAS) and Tianjin Medical University has uncovered a potential therapeutic strategy for bone deterioration disorders. The research team identified a small-molecule compound that specifically inhibits the assembly of the PRC1.1 complex, thereby enhancing bone remodeling. The findings were published in Nature Communications.

Polycomb Repressive Complexes (PRCs), primarily comprising PRC1 and PRC2, are critical epigenetic regulators that maintain cell identity and contribute to tumorigenesis by repressing the transcription of target genes. However, the precise roles of PRCs in cancer and other diseases, as well as the therapeutic potential of targeting these complexes, remain areas of active investigation.

In this study, researchers discovered that the aberrant activation of PRC1.1, a non-canonical PRC1 complex, is closely linked to impaired ossification during aging. In activation of KDM2B, a core subunit of PRC1.1, significantly promoted bone formation by reducing H2AK119ub1 levels and alleviating suppression of the Wnt/β-catenin pathway.

Building on this insight, the team developed a small-molecule compound named iBP, which disrupts PRC1.1 assembly by inhibiting the interaction between BCOR and PCGF1, thereby suppressing PRC1.1 activity. In a mouse model of ovariectomy, which simulates osteoporosis, iBP effectively reversed bone loss. Additionally, in a bone trauma mouse model, iBP accelerated bone healing and promoted new bone formation.

The research not only deepens our understanding of PRC1.1's role in bone metabolism but also provides a strong foundation for the development of novel therapeutic agents targeting bone diseases.

This study was supported by National Key Research and Development Program, Basic Research Project of Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, among others.

Figure. Compound iBP disrupts activity of PRC1.1 by inhibiting the its assembly, thereby promoting bone remodeling (Image by Prof. LIU’s team)

Contacts:

LIU Jinsong, Ph.D., Principal Investigator;

Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China, 510530.

Email: liu_jinsong@gibh.ac.cn