SHP2-IN-13 is an orally active, highly selective allosteric inhibitor targeting the SHP2 “tunnel site,” exhibiting an IC50 of 83.0 nM. It holds potential for research into cancers with RTK oncogenic drivers and diseases associated with SHP2.

SHP2-IN-13 (compound 129) effectively inhibits the pERK signaling pathway in a dose-dependent manner, with IC50 values of 0.59 μM in NSCLC cells and 0.63 ± 0.32 μM in NCI-H1975-OR cells [1]. At concentrations from 0 to 30 μM over 24 hours, it suppresses pERK levels and RTK-driven proliferation in NCI-H1975 cells and inhibits pERK levels in RTK-resistant NSCLC cells [1].

In pharmacokinetic studies, SHP2-IN-13 (compound 129) (IV/PO; 5mg/kg) demonstrated high clearance, substantial volume of distribution (13.9 L/kg), and a moderate half-life (T 1/2 = 5.31 h), with oral bioavailability (F= 55.07±7.93%) exceeding that of SHP099 (F= 46%), making it suitable for further in vivo antitumor pharmacodynamic evaluation [1]. SHP2-IN-13 (oral gavage; 20 mg/kg; daily) exhibited potent anti-leukemic efficacy, which significantly reduced leukemic burden, and nearly eradicated CD45+ leukemic cells from human blood and spleen samples [1].