SHP2-D26 is a highly potent and effective SHP2 degrader. Its mechanism of action involves the induction of SHP2 degradation through binding to VHL-1 and SHP2 proteins. Additionally, the degradation of SHP2 induced by SHP2-D26 is dependent on neddylation and proteasome activity.

SHP2-D26 effectively decreases SHP2 protein levels in a dose-dependent manner across different concentrations (0, 3, 10, 30, 100, 300 nM over 12 hours) and time points (0-24 hours at 100 nM), as demonstrated in KYSE520 and MV-4-11 cells. Notably, SHP2 protein reduction initiates within 4 hours, achieving full depletion by 8 hours when treated with 100 nM. Moreover, dose-response analysis reveals DC50 values of 6.0 nM for KYSE520 cells and 2.6 nM for MV-4-11 cells, respectively. In a separate 4-day cell proliferation assay using a range of 0-100 μM for KYSE520 cells and 0-10 nM for MV-4-11 cells, IC50 values were determined to be 0.66 μM for KYSE520 cells and 0.99 nM for MV-4-11 cells, indicating significant anti-proliferative effects at these concentrations[1].