AZ-5104

AZ-5104 is an active, demethylated metabolite of AZD 9291. AZ-5104 is an EGFR inhibitor with IC₅₀s of 1, 6, 1, 25 and 7 nM for EGFR^L858R/T790M, EGFR^L858R, EGFR^L861Q, EGFR and ErbB4, respectively. IC50 & Target:IC50: 1 nM (EGFR^L858R/T790M), 6 nM (EGFR^L858R),1 nM EGFR^L861Q,1 nM (EGFR),1 nM (ErbB4)^[1] In Vitro:AZ-5104 inhibits EGFR phosphorylation with IC₅₀s of 2, 1, 2, 53, and 33 nM in H1975 (EGFR^L858R/T790M), PC-9VanR (EGFR^{Exon 19 deletion/T790M}), PC-9 (EGFR^{Exon 19 deletion}), H2073 (WT), and LOVO (WT), respectively. AZ5104 exhibits a reduced selectivity margin against wild-type EGFR when compared to AZD9291. AZ5104 display minimal off-target activity against other non-HER family kinases, but has the potential to target both HER2 and HER4 kinase activity^[1]. In Vivo:The metabolite, AZ5104 (5 mg/kg/day), is effective in shrinking tumors in both C/L858R and C/L+T mice^[1].