biostudies-literatureCho HJUK Research and Innovation (UKRI)British Heart FoundationCancer Research UKBarts CharityMedical Research CouncilNIHR | National Institute for Health and Care Research Applied Research Collaboration Oxford and Thames ValleyUK Research and InnovationUKRI | Medical Research Council2115-2136https://www.ebi.ac.uk/biostudies/studies/S-EPMC12340136biostudies-literatureUnknown17(8)Activating mutations of Src homology-2 domain-containing protein tyrosine phosphatase-2 (Shp2) cause multiple childhood conditions for which there is an unmet therapeutic need, including juvenile myelomonocytic leukemia (JMML) and Noonan syndrome. SFX-01, an α-cyclodextrin-stabilized sulforaphane complex currently in clinical development, covalently adducts cysteine residues. Using unbiased proteomics, its protein targets were identified, including Shp2. SFX-01 induced an inhibitory dithiolethione modification at the Shp2 active site cysteine. Importantly, in a transgenic mouse model of human Noonan syndrome with hyperactive D61G Shp2, SFX-01 concomitantly normalized their phosphatase activity and myeloid cell count. Furthermore, SFX-01 also attenuated JMML human patient-derived hematopoieEMBO molecular medicineSFX-01 is therapeutic against myeloproliferative disorders caused by activating mutations in Shp2.PMC12340136EP/Y027698/1MR/R01065X/2C16420/A18066MGU0401Cardiovascular Programme Award G00913Schroder EYin XLynham SPrysyazhna OFernandez-Caggiano MCutillas PRLouka ESwitzer CHEaton PSmith JMayr MBianchi KYang XMead AJRajeeve Vde Jesus DSCho HJMorales VCharles RLEminaga SfalseSFX-01 is therapeutic against myeloproliferative disorders caused by activating mutations in Shp2.Activating mutations of Src homology-2 domain-containing protein tyrosine phosphatase-2 (Shp2) cause multiple childhood conditions for which there is an unmet therapeutic need, including juvenile myelomonocytic leukemia (JMML) and Noonan syndrome. SFX-01, an α-cyclodextrin-stabilized sulforaphane complex currently in clinical development, covalently adducts cysteine residues. Using unbiased proteomics, its protein targets were identified, including Shp2. SFX-01 induced an inhibitory dithiolethione modification at the Shp2 active site cysteine. Importantly, in a transgenic mouse model of human Noonan syndrome with hyperactive D61G Shp2, SFX-01 concomitantly normalized their phosphatase activity and myeloid cell count. Furthermore, SFX-01 also attenuated JMML human patient-derived hematopoie2025-01-01T00:00:00Z2025 Aug2026-05-29T17:55:43.117Z2026-05-18T03:07:20.623ZS-EPMC123401364064054710.1038/s44321-025-00267-7