Key result
A high-throughput screening method using a HEK293 stable cell line was successfully developed and optimized to identify small-molecule inhibitors of myostatin and activin A.
The development of a high-throughput screening method enables the identification of small-molecule inhibitors targeting myostatin and other TGF-β family ligands for potential treatment of muscle-wasting diseases.
Provides validated 384-well HTS assay for myostatin/activin A inhibitors; leaves open whether hits will yield clinical therapies.
Myostatin, a member of the transforming growth factor (TGF)-β family of secreted ligands, is a strong negative regulator of muscle growth. As such, therapeutic inhibitors of myostatin are actively being investigated for their potential in the treatment of muscle-wasting diseases such as muscular dystrophy and sarcopenia. Here, we sought to develop a high-throughput screening (HTS) method for small-molecule inhibitors that target myostatin. We created a HEK293 stable cell line that expresses the (CAGA)12-luciferase reporter construct and robustly responds to signaling of certain classes of TGF-β family ligands. After optimization and miniaturization of the assay to a 384-well format, we successfully screened a library of compounds for inhibition of myostatin and the closely related activin A. Selection of some of the tested compounds was directed by in silico screening against myostatin, which led to an enrichment of target hits as compared with random selection. Altogether, we present an HTS method that will be useful for screening potential inhibitors of not only myostatin but also many other ligands of the TGF-β family.
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Cash et al. (2013) studied Muscle-wasting diseases (muscular dystrophy and sarcopenia). High-throughput screening (HTS) method was evaluated on Inhibition of myostatin and activin A. A high-throughput screening method using a HEK293 stable cell line was successfully developed and optimized to identify small-molecule inhibitors of myostatin and activin A.
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