IACS-13909 (IACS13909) is a potent, and selective allosteric inhibitor of SHP2 with IC50 of 15.7 nM (hSHP2 full length), Kd of 32 nM (ITC).
IACS-13909 potently suppresses the phosphatase activity of purified full-length, recombinant human SHP2 protein with an IC50 of 15.7 nM.
IACS-13909 does not suppress SHP2 phosphatase activity at 10 uM, acts outside the phosphatase domain.
IACS-13909 displays no inhibitory activity against a panel of 22 phosphatases, and no inhibition of full-length SHP1.
IACS-13909 inhibits the proliferation and MAPK pathway signaling of tumor cell lines driven by a broad spectrum of RTKs in vitro (GI50<100 nM, DK-MG (EGFR vIII+), BV-173 (BCR-ABL), KG-1 (OP2-FGFR1), KU812 (BCR-ABL), SW-13 (ERBB4-IKZF2) and MV-4-11 (FLT3-ITD)).
IACS-13909 inhibits the proliferation and MAPK pathway signaling in RTK-activated cancer cells in vitro due to on-target SHP2 inhibition.
IACS-13909 demonstrates antitumor activity in tumors harboring EGFR-dependent resistance mutation in vitro and in vivo.