Poziotinib

• CAT Number: I000381
• CAS Number: 1092364-38-9
• Molecular Formula: C23H21Cl2FN4O3
• Molecular Weight: 491.34
• Purity: ≥95%
• Synonyms: 1-[4-[4-(3,4-dichloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]prop-2-en-1-one
• InChI: InChI=1S/C23H21Cl2FN4O3/c1-3-20(31)30-8-6-13(7-9-30)33-19-10-14-17(11-18(19)32-2)27-12-28-23(14)29-16-5-4-15(24)21(25)22(16)26/h3-5,10-13H,1,6-9H2,2H3,(H,27,28,29)
• InChIKey: LPFWVDIFUFFKJU-UHFFFAOYSA-N
• SMILES: COC1=C(C=C2C(=C1)N=CN=C2NC3=C(C(=C(C=C3)Cl)Cl)F)OC4CCN(CC4)C(=O)C=C

Poziotinib (HM781-36B) is an orally active, irreversible pan-HER inhibitor, which effectively inhibits EGFRwt, 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 EGFRT790M and EGFRL858R/T790M, with IC50s of 4.2 and 2.2 nM, respectively. Excellent antitumor activity[1][2].
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].
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].

Reference

[1]. Nam HJ, et al. Antitumor activity of HM781-36B, an irreversible Pan-HER inhibitor, alone or in combination with cytotoxic chemotherapeutic agents in gastric cancer. Cancer Lett. 2011 Mar 28;302(2):155-65.
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[2]. Cha MY, et al. Antitumor activity of HM781-36B, a highly effective pan-HER inhibitor in CP-358774-resistant NSCLC and other EGFR-dependent cancer models. Int J Cancer. 2012 May 15;130(10):2445-54.
 [Content Brief]

[3]. Kang MH, et al. Antitumor Activity of HM781-36B, alone or in Combination with Chemotherapeutic Agents, in Colorectal Cancer Cells. Cancer Res Treat. 2015 Mar 5.
 [Content Brief]