Transforming growth factor beta isoforms (TGF-β1, -β2, -β3) regulate the adaptive immune system and coordinate wound healing, functions that are essential for the long-term survival of humans and other vertebrates. They also play prominent roles in human disease, especially cancer, where they function as tumor suppressors in normal and early neoplastic cells, but as promoters of tumor growth and metastasis in established cancers. TGF-βs also coordinately upregulate the expression of many matrix proteins, such as collagen and fibronection, as well as tissue inhibitors of matrix mettaloproteinases (TIMPs), and have been shown to play a causative role in the progression of many fibrotic disorders, including kidney and pulmonary fibrosis. TGF-β’s disease-promoting activities have made it an important molecular target for treatment of cancer and fibrosis, yet no inhibitors have been FDA-approved.
The Hinck laboratory is working to develop novel small molecule assembly inhibitors as alternatives to TGF-β receptor kinase inhibitors since the latter target many other kinases and accordingly have a relatively narrow therapeutic window. The Hinck laboratory is taking the alternative approach of employing fluorescence TR-FRET based high throughput screening (HTS) and NMR based fragment screening (FBDD) to identify small molecules that bind to TGF-β or the TGF-β receptors and block assembly of the TGF-β signaling complex. The advantage of this approach for inhibiting TGF-β compared with other types of small molecule inhibitors, such as TβRI and TβRII kinase inhibitors, is increased specificity since they target the TGF-β receptor complex, which is distinct compared to other proteins of the superfamily. This research project is is highly inter-disciplinary in nature, involving a combination of NMR, X-ray crystallography, medicinal chemistry, and cell-based functional assays.