ZW-49

ZW-49 is a pan-EGFR inhibitor with oral bioavailability, showing IC50 values ranging from 0.03 to 1.5 nM. It effectively inhibits all EGFR mutant subtypes and demonstrates selectivity for wild-type EGFR and other target families. ZW-49 blocks the ATP binding site and occupies a conserved hydrophobic sub-pocket, preventing steric clashes with P-loop mutations (PACC). It suppresses cancer cell proliferation, induces G0/G1 cell cycle arrest and apoptosis, and exhibits antiproliferative activity in xenograft mouse models. ZW-49 is applicable in cancer research, including studies on non-small cell lung cancer.

ZW-49 is a potent inhibitor of a broad range of mutant EGFR kinases, with an IC50 of 1.5 nM for EGFR L858R/T790M and a selectivity of 6.6-fold for wild-type EGFR (IC50 = 9.9 nM), and also targets specific HER2 mutants. ZW-49 (72 h) effectively inhibits the proliferation of EGFR mutant cell lines, such as NCI-H1975 (IC50 = 12 nM) and HCC827 (IC50 = 4 nM), and acts on Ba/F3 cells with non-classical EGFR mutations (IC50 = 0.58-5.59 nM), in addition to inhibiting HER2 overexpressing cells. ZW-49 (1-1000 nM; 2 h) robustly and dose-dependently inhibits EGFR phosphorylation and downstream AKT/ERK signaling pathways in EGFR mutant cell lines, including those with non-classical mutations like NCI-H1975, HCC827, and Ba/F3 cells. ZW-49 (0.01-1 μM) induces G0/G1 cell cycle arrest and apoptosis in H1975 cells.

ZW-49 (5-25 mg/kg; orally; once daily; for 2 weeks) effectively inhibits tumor growth in various cancer xenograft mouse models.