NST-628 is a pan-RAF-MEK molecular glue that prevents RAF from phosphorylating and activating MEK, inhibiting the RAF-MEK signaling complex.

NST-628 demonstrates elevated antiproliferative activity in BRAF Class II/III mutant cell models compared to other RAF and MEK inhibitors, without promoting heterodimer formation of BRAF and CRAF. [1]
NST-628 (4-100 nM; 48 h) induces early and late apoptosis in a dose-dependent manner and decreases live cell populations in NRAS mutant IPC-298 and SK-MEL-2, NF1 mutant MeWo, and KRAS mutant HCT116 cell lines. [1]

NST-628 when administered orally (p.o.) at doses of 3 mg/kg and 5 mg/kg once daily (qd), or 1.5 mg/kg twice daily (b.i.d), significantly slowed tumor growth in models with KRAS and NRAS mutations. In the SK-MEL-2-luc model, it caused tumor regression. [1]
Administered intragastrically (i.g.) at 0.3-3 mg/kg once daily for 18-20 days, NST-628 inhibited the RAS-MAPK pathway in mice in a dose-dependent manner, showing strong anti-tumor activity in the MeWo-luc model. At a dose of 2 mg/kg once daily for 26 days in an NCI-H23 KRASG12C-mutant lung adenocarcinoma model, NST-628 effectively slowed tumor growth and significantly inhibited the RAS-MAPK pathway. [1]