• Activating mutations of Shp2 cause conditions such as Noonan syndrome and juvenile myelomonocytic leukemia (JMML), with unmet therapeutic needs. • SFX-01, a sulforaphane complex, modifies cysteine residues and targets proteins including Shp2, where it induces an inhibitory modification at the active site of this protein phosphatase. • In a transgenic mouse model of Noonan syndrome and human JMML stem cells, SFX-01 normalized Shp2 activity, reduced myeloid cell counts, and induced cell-cycle arrest, highlighting its therapeutic potential.