AV-412 (MP412) is an EGFR inhibitor for EGFR, EGFR T790M, EGFR L858R, EGFR L858R/T790M, and ErbB2, with IC50 values of 0.75, 0.79, 0.5, 2.3, and 19 nM, respectively.

EGFR (L858R):0.5 nM, EGFR:0.75 nM, EGFR (T790M):0.79 nM, ErbB2:19 nM, EGFR (L858R/T790M):2.3 nM

In cells, MP-412 inhibited autophosphorylation of EGFR and ErbB2 with IC(50) of 43 and 282 nM, respectively. It also inhibited epidermal growth factor (EGF)-dependent cell proliferation with an IC(50) of 100 nM. Moreover, MP-412 abrogated EGFR signaling in the gefitinib-resistant H1975 cell line, which harbors a double mutation of L858R and T790M in EGFR.

In animal studies using cancer xenograft models, MP-412 (30 mg/kg) demonstrated complete inhibition of tumor growth in A431 and BT-474 cell lines, which overexpress EGFR and ErbB2, respectively. MP-412 suppressed EGFR and ErbB2 autophosphorylation at doses corresponding to its antitumor efficacy. Various dosing schedules showed significant effects with daily and every-other-day schedules, but not with a once-weekly schedule, suggesting frequent dosing is preferable. Additionally, MP-412 exhibited significant antitumor effects on the ErbB2-overexpressing KPL-4 breast cancer cell line, which is resistant to gefitinib. These studies indicate MP-412's potential as a therapeutic for cancers expressing EGFR and ErbB2, especially those resistant to first-generation small-molecule inhibitors.