AV-412 (free base)

AV-412 free base (MP-412 free base) is an EGFR inhibitor with IC₅₀s of 0.75, 0.5, 0.79, 2.3, 19 nM for EGFR, EGFR^L858R, EGFR^T790M, EGFR^L858R/T790M and ErbB2, respectively. IC50 & Target: IC50: 0.75 nM (EGFR), 0.5 nM (EGFR^L858R), 0.79 nM (EGFR^T790M), 2.3 nM (EGFR^L858R/T790M), 19 nM (ErbB2)^[1] In Vitro: AV-412 inhibits autophosphorylation of EGFR and ErbB2 with IC₅₀ of 43 and 282 nM, respectively. AV-412 also inhibits epidermal growth factor (EGF)-dependent cell proliferation with an IC₅₀ of 100 nM. AV-412 abrogates EGFR signaling in the gefitinib-resistant H1975 cell line, which harbors a double mutation of L858R and T790M in EGFR^[1]. In Vivo: In animal studies using cancer xenograft models, AV-412 (30 mg/kg) demonstrates complete inhibition of tumor growth of the A431 and BT-474 cell lines, which overexpress EGFR and ErbB2, respectively. AV-412 suppresses autophosphorylation of EGFR and ErbB2 at the dose corresponding to its antitumor efficacy. When various dosing schedules are applied, AV-412 shows significant effects with daily and every-other-day schedules, but not with a once-weekly schedule, suggesting that frequent dosing is preferable for this compound. Furthermore, AV-412 shows a significant antitumor effect on the ErbB2-overexpressing breast cancer KPL-4 cell line, which is resistant to gefitinib^[1].