SFX-01 is therapeutic against myeloproliferative disorders caused by activating mutations in Shp2

Hyun Ju, Cho, Joy, Smith, Christopher H., Switzer, Eleni, Louka, Rebecca L., Charles, Oleksandra, Prysyazhna, Ewald, Schroder, Mariana, Fernandez-Caggiano, Daniel Simoes, de Jesus, Seda, Eminaga, Xiaoke, Yin, Xiaoping, Yang, Steven, Lynham, Manuel, Mayr, Valle, Morales, Katiuscia, Bianchi, Vinothini, Rajeeve, Pedro R., Cutillas, Adam J., Mead, Philip, Eaton

EMBO Molecular Medicine |

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 hematopoietic stem cell proliferation that was linked to STAT1 signaling and decreased cyclin D1 expression, resulting in cell-cycle arrest. We conclude that SFX-01 is an activating mutant Shp2 inhibitor and may offer beneficial effects in patients with JMML or Noonan syndrome.