PTPN11 activating mutations stand out as the predominant genetic anomaly in JMML, affecting nearly 40% of patients. The PTPN11 gene encodes SHP2, a critical protein tyrosine phosphatase integral to regulating the RAS signaling pathway. Individuals harboring PTPN11 mutations exhibit the most aggressive JMML forms, marked by a high relapse rate post-HSCT and a five-year overall survival of merely 25%.

While SHP2-specific inhibitors have shown promise as therapeutic options for RAS-dependent tumors, their efficacy against hyperactive SHP2 mutant forms, prevalent in JMML, remains limited. The primary goal of this project is identifying novel small-molecule compounds capable of effectively restraining the aberrant activity of mutant SHP2. This pursuit aims to offer a promising therapeutic alternative for treating JMML, addressing a critical gap in current treatment strategies.