Poziotinib

Poziotinib (HM781-36B) is an orally active, irreversible pan-HER inhibitor, which effectively inhibits EGFR^wt, HER-2 and HER-4 with IC₅₀s of 3.2, 5.3 and 23.5 nM, respectively. Poziotinib (HM781-36B) also shows excellent inhibitory activities against mutated EGFRs, including EGFR^T790M and EGFR^L858R/T790M, with IC₅₀s of 4.2 and 2.2 nM, respectively. Excellent antitumor activity^[1][2]. IC50 & Target:IC50: 3.2 nM (EGFR^wt), 5.3 nM (HER-2), 23.5 nM (HER-4) 4.2 nM (EGFR^T790M), 2.2 nM (EGFR^L858R/T790M)^[2] In Vitro: The IC₅₀ levels of Poziotinib (HM781-36B) for N87 and SNU216 were 0.001 and 0.004 μM, respectively, which was 10-1000 fold lower than the IC₅₀ levels of other HER family TKIs. HM781-36B more potently inhibited the phosphorylation of HER family and downstream proteins, and induced apoptosis and G1 arrest compared to ZD1839 or GW572016^[1].
Poziotinib (HM781-36B) also shows excellent selectivity with other kinases with greater than 100- to 1,000- fold IC₅₀ values compared with EGFR family members. Poziotinib (HM781-36B) possesses a functional α,β‐unsaturated carbonyl group as Michael acceptor moiety at the C6 position that allows covalent modifications of the EGFR kinase domain active site^[2].
The addition of HM781-36B induced potent growth inhibition in both DiFi cells with EGFR overexpression and SNU-175 cells (IC₅₀=0.003 and 0.005 μM, respectively). Furthermore, HM781-36B induced G1 arrest of the cell cycle and apoptosis, and reduced the levels of HER family and downstream signaling molecules, pERK and pAKT, as well as nonreceptor/cytoplasmic tyrosine kinase, BMX^[3]. In Vivo: The growth of tumors in mice treated with HM781-36B alone or in combination with 5-FU was significantly inhibited compared with control mice, and tumor volume in mice receiving coadministraion of HM781-36B and 5-FU was smaller than tumor volume in mice receiving HM781-36B only^[1].