EGFR-IN-2

EGFR-IN-2 is a a noncovalent, irreversible, mutant-selective second generation EGFR inhibitor. IC50 & Target: EGFR^[1] In Vitro: EGFR-IN-2 (Compound 21) inhibits EGFR autophosphorylation with IC₅₀s of 0.027 μM, 0.009 μM ,0.033 μM , and 0.218 μM in double mutant TMLR cell line H1975, double mutant TMdel cell line PC9-ER, activating mutant del cell line PC9, and wild type cell line H292. In addition, EGFR-IN-2 demonstrats strong antiproliferative effect on the T790M mutant carrying H1975 cell line (IC₅₀=0.361 μM) and the single activating mutant PC9 cell line (IC₅₀=0.151 μM). Furthermore, EGFR-IN-2 also shows good selectivity against other kinases when evaluated in a 225-kinase panel (12/225 kinases inhibited at >70% when tested at 0.1 μM, 61-fold over the TMLR K_i and 63-fold over the TMdel K_i)^[1]. In Vivo: To examine its inhibitory effect on pEGFR levels in vivo, EGFR-IN-2 (Compound 21) is studied in a mouse H1975 (TMLR) xenograft model. After a single oral dose of 21 at 50 mg/kg, free plasma concentrations of EGFR-IN-2 at or exceeding the in vitro p-EGFR IC₅₀ of 0.027 μM are sustained over 8 h. When administered at 100 mg/kg, the coverage of p-EGFR IC₅₀ is extended to the last measured time point of 16 h postdose. Corresponding knockdown of p-EGFR and the downstream effectors pERK1/2 and AKT levels are observed at those time points, suggesting target engagement in vivo. In mouse, after intravenous and oral administration, the plasma clearance of EGFR-IN-2 is determined to be 104 mL/kg per min with a bioavailability of 19%. In dogs, the plasma clearance is 13 mL/kg per min with an oral bioavailability of 30%^[1].