Figure 1. IACS-13909 is a potent and selective allosteric inhibitor of SHP2.

(A) The structure of IACS-13909. (B) Dose response of IACS-13909 in an in vitro enzymatic assay with purified full-length human SHP2, in the presence of 1 μM bistyrosylphorphorylated peptide. The dose response curve is from a single representative experiment. The IC₅₀ is calculated from 59 independent tests. (C) The effect of IACS-13909 in an in vitro enzymatic assay with purified, human SHP2 phosphatase domain. N=10. Since 50% inhibition was not achieved, IC₅₀ was defined as above the top tested concentration. (D) Crystal structure of IACS-13909 with purified human SHP2 protein, at 2.4 A°, determined by X-ray crystallography. PDB=6WU8. The phosphatase domain is highlighted in grey, C-SH2 in cyan and N-SH2 in green. (E) The impact of IACS-13909 on pERK^T202/Y204 and pMEK1/2^S217/221 levels in KYSE-520 cells overexpressing dsRED (control), SHP2 WT or SHP2 P491Q mutant. Cells were treated with IACS-13909 for 2 hours and processed for Western blotting. (F) The in vitro anti-proliferative effect of IACS-13909 on cells used in E, determined by a 14-day clonogenic assay. N=2 from the same experiment. This experiment has been repeated with another allosteric SHP2 inhibitor with similar observation.