HCD3514 is a novel potent, selective, fourth-generation EGFR inhibitor targeting C797S triple mutation, strongly inhibits EGFRL858R/T790M/C797S and EGFR19del/T790M/C797S mutations with IC50 of 1.0 and 2.0 nM, respectively.
HCD3514 displays 78-fold selectivity over EGFR WT (IC50=156 nM), possesses more potent kinase inhibitory activity against EGFR triple mutations than brigatinib.
HCD3514 potently inhibited the proliferation of BaF3-EGFRL858R/T790M/C797S and BaF3-EGFR19del/T790M/C797S cells with IC50 of 0.35 μM and 0.25 μM, respectively, with little effect on BaF3 parental cells (IC50=1.31 uM).
HCD3514 also displayed an excellent antiproliferative potency in PC-9-OR cells, with IC50 of 0.48 μM, which was similar to that of brigatinib (IC50=0.40 μM) and more potent than AZD9291 (IC50=6.30 μM).
HCD3514 potently and dose-dependently suppressed the EGFR phosphorylation in both triple mutant BaF3 cells and PC-9-OR cells.
HCD3514 triggered significant apoptosis with apoptosis rates of 72.39% and 98.27% at 1 uM and 3 uM in BaF3-EGFRL858R/T790M/C797S cells, respectively.
HCD3514 (50 and 75 mg/kg, oral) suppressed tumor growth in EGFRC797S triple mutant BaF3 xenograft model.
HCD3514 potently inhibited EGFRL858R/T790M and EGFR19del/T790M mutations with IC50 values of 4.9 and 8.9 nM in biochemical, respectively.
HCD3514 showed antiproliferative activities in BaF3-EGFRL858R/T790M and BaF3-EGFR19del/T790M cells with IC50 of 0.66 μM and 0.52 μM, respectively.
HCD3514 exhibited in vitro anti-tumor activity of HCD3514 in NCI-H1975 cells harboring EGFRL858R/T790M (IC50=0.49 uM).