Naquotinib (ASP8273) (ASP8273) is an orally available, mutant-selective and irreversible EGFR inhibitor; (IC50s: 8-33 nM and 230 nM toward EGFR mutants and EGFR.

EGFR:230 nM, EGFR (mutants):8-33 nM

In studies utilizing cells inherently dependent on EGFR, Naquotinib effectively hinders the proliferation of various cancer cell lines, including PC-9(del ex19), HCC827(del ex19), NCI-H1975(del ex19/T790M), and PC-9ER(del ex19/T790M), demonstrating IC50 values ranging from 8 to 33 nM [1]. It specifically targets and suppresses the phosphorylation of EGFR along with the subsequent activation of the ERK and Akt signaling pathways, starting at concentrations as low as 10nM in HCC827 and NCI-H1975 cells. However, this effect requires a much higher concentration of 1000nM in A431 cells. Notably, in NCI-H1650 (del ex19) cells, Naquotinib significantly curtails cell growth with an IC50 value of 70nM, showing its efficacy where other EGFR-TKIs have limited effectiveness [2].

In NCI-H1975 (L858R/T790M), HCC827 (del ex19), and PC-9 (del ex19) xenograft models, oral administration of Naquotinib results in dose-dependent tumor regression, with the dosing schedules having no impact on its efficacy. Specifically, in an NCI-H1975 xenograft model, Naquotinib leads to complete tumor regression after a 14-day treatment period. Remarkably, 50% of the mice maintain complete regression for over 85 days following the cessation of Naquotinib treatment [2].