Personalized, targeted therapy for RASopathies by Inhibition of protein-protein interactions of the SHP2 phosphatase.

RASopathies are a group of genetic conditions that together rank among the most common “rare” diseases. They can affect the heart and lymphatic system, increase cancer risk, and cause short stature, distinct facial features, and learning delays. Symptoms after birth vary widely, from very mild to life-threatening. For instance, many young patients develop severe heart muscle thickening that often leads to fatal heart failure. Currently, there is no cure. At the root of all RASopathies are mutations in the proteins that transmit messages inside our cells, causing excessive and unregulated signaling. One of the most critical is SHP2, a molecule that helps relay signals from cell-surface receptors into the cell interior. Our project sets out to design, optimize and develop molecules that block SHP2’s interactions with other proteins, and thus reduce signal transmission. By combining biophysics, synthetic chemistry, molecular biology, and cell biology in a truly multidisciplinary approach, we’ll design, optimize, and rigorously test these inhibitors in the lab. By the project’s end, we aim to have lead compounds fully characterized and ready for preclinical and clinical development by pharmaceutical partners. This work could lay the groundwork for the first targeted treatments—and ultimately a cure—for all children living with RASopathies.