Lazertinib (GNS-1480) is an effective, highly mutant-selective and irreversible EGFR-TKI with IC50 values of 1.7 nM, 2 nM, 5 nM, 20.6 nM and 76 nM for Del19/T790M, L858R/T790M, Del19, L85R and Wild type EGFR respectively.

In NSCLC cell lines and primary cancer cells from patients harbouring EGFR mutations, YH25448 more potently inhibits cancer cell growth and significantly increases tumour cell apoptosis compared to osimertinib[1]. In the cell proliferation assays, GI50 values of Lazertinib are 6 nM, 5 nM, and 711 nM for H1975 cells (L858R/T790M), PC9 cells (del19) and H2073 cells (wt), respectively.

In an in vivo mouse model implanted with H1975 cells, once-daily YH25448 treatment results in dramatic dose-dependent tumour regression in both subcutaneous and intracranial lesions with no abnormal signs such as skin keratosis. The plasma half-life of YH25448 is 5.9-6.8 hr, while a tumour to plasma AUC0-last ratio is 3.0-5.1 in tumour-bearing mice. YH25448 shows excellent penetration of the blood-brain barrier, achieving CSF concentrations exceeding the IC50 value for pEGFR inhibition. YH25448 shows superior efficacy for tumour regression in an EGFR mutant brain metastasis model[1].

Concentrations: 5, 10, 100 nM. Ba/F3 cells overexpressing the indicated EGFR mutant are treated with YH25448 or osimertinib for 6 hours at the indicated concentrations. pEGFR levels are detected by Western blot analysis.