A test system to identify bone morphogenic protein (BMP)-mimetics
Small molecule activators of the Bone Morphogenetic Protein (BMP)-signaling pathway hold promise for many applications in stem cell research such as (cost-)efficient and robust mesodermal differentiation from pluripotent stem cells (e.g., ESCs, iPSCs) or as therapeutics for degenerative bone (and cartilage) diseases (please see relevant publications).
In this context, a phenotypic assay in murine embryonic stem cells, designed to combine assets of a high-throughput format with physiological (morphogenetic) relevance was developed to identify BMP-mimetics. A chemical biology approach employing known cardiogenic compounds enabled the characterization of BMP signaling selectivity compared to other develop-mental pathways for the first time in this assay system. Mechanistic as well as technical assay parameters were optimized and allowed pilot-screening of a 1,408 compounds-comprising library. Ten small molecule BMP mimetics were identified and validated via IC50 determination and a set of orthogonal assays. Their utility as chemical tools for stem cell technologies and as regenerative therapeutics will have to be explored in future studies.
Ready-to-screen assay format for up to 50,000 compounds comprising libraries. In addition, several functionally validated BMP mimetic compounds have been identified, including first profiling of structure-activity relationships by means of medicinal chemistry.
- Unique, innovative, stem cell-based assay for the identification of BMP-mimetic agents
- Ligand-independent BMP-mimetic compounds with novel mode-of-action
The test system as well as novel BMP-mimetic compounds are offered for licensing and further biotechnological and/or therapeutic development.
Publikationen & Verweise
Feng, L., et al. (2016) Discovery of a small-molecule BMP sensitizer for human embryonic stem cell differentiation. Cell Reports 15: 2063-75.
Ali, I.H. & Brazil, D.P. (2014) Bone morphogenetic proteins and their antagonists: current and emerging clinical uses. British Journal of Pharmacology 171: 3620-32.
StichworteStammzelle, Differenzierung, induzierte pluripotente Stammzelle, mesenchymal, osteogen, stem cell, differentiation, induced pluripotent stem cell, mesenchymal, bone morphogenic proteins