Scholar Rock® has developed proprietary technology based on new insights into the structural biology and activation mechanisms of protein growth factors.
Growth factors have been widely recognized as disease targets because of their fundamental roles in regulating cell growth and differentiation, but only recently have new insights into the complex biology of their activation been discovered. Scholar Rock’s innovative approach integrates a holistic understanding of:
the diverse structures of the latent complexes in which growth factors are stored extracellularly
the tissue-specific macromolecular context of latent complexes ensuring that growth factor activation occurs locally (“supracellularly”) at the site of disease rather than throughout the body
Scholar Rock’s deep understanding into the critical steps of growth factor activation in the supracellular context opens new ways for therapeutic targeting of latent complexes in the local microenvironment to discover and develop growth factor modulators that intervene at this activation step.
A prime example: Novel targeting of Transforming Growth Factor-beta (TGFβ)
TGFβ1 is a growth factor that is first produced by cells in a precursor form known as a proform. The proform is then processed by the cell into the mature growth factor and a propeptide. The cell then secretes a complex consisting of the mature growth factor in physical association with the propeptide. This complex is inactive or “latent,” and in 2011, the laboratory of Professor Timothy Springer at the Harvard Medical School and Boston Children’s Hospital discovered the structure of this complex and the molecular basis for how this inactive complex is activated supracellularly:
Normal activation of latent TGFβ via integrin binding
A new way to target disease
Traditional therapeutic approaches directly target a growth factor or its receptor everywhere in the body, not only shutting down its harmful function in disease, but also causing undesirable side effects arising from the inherent biology of growth factors: individual growth factors occur as members of larger families of structurally related proteins and a single growth factor can elicit a different biological effect in different tissues. By targeting the latent growth factor complexes that are located in the microenvironment of specific types of cells and tissues, their supracellular context, Scholar Rock’s drug candidates are able to result in highly specific and local therapeutic effects. Importantly, unlike conventional inhibitors, supracellular activation can be the subject of therapeutic modulation either by inhibitors in cases of excess growth factor activity, or by activators in cases of deficient growth factor activity.
For the first time, Scholar Rock's approach is targeting growth factor activation from the latent complex to open up a new therapeutic approach to address challenging diseases.
Scholar Rock's modulation of supracellular activation targets novel features of key disease-causing proteins and opens up a new therapeutic approach to address challenging diseases.