product name Poziotinib (HM781-36B)
Description: Poziotinib (also known as HM781-36B and NOV120101, HM781-36B) is an orally bioavailable, quinazoline-based, irreversible pan-HER inhibitor with IC50 of 3.2 nM, 5.3 nM and 23.5 nM for HER1, HER2, and HER4, respectively. HM781-36B irreversibly inhibits EGFR (HER1 or ErbB1), including EGFR mutants, HER2, and HER4, thereby inhibiting the proliferation of tumor cells that overexpress these receptors. EGFRs, cell surface receptor tyrosine kinases, are often upregulated in a variety of cancer cell types and play key roles in cellular proliferation and survival.
References: Cancer Lett. 2011 Mar 28;302(2):155-65; Int J Cancer. 2012 May 15;130(10):2445-54.
491.34
Formula
C23H21Cl2FN4O3
CAS No.
1092364-38-9
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 98 mg/mL (199.5 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)
Synonyms
NOV120101, HM781-36B
other peoduct :References PubMed ID：:http://www.ncbi.nlm.nih.gov/pubmed/19416716
| In Vitro |
In vitro activity: Poziotinib specifically inhibits the cell growth in HER2 amplified gastric cancer cells, and inhibits the phosphorylation of EGFR and key components of downstream signaling cascades such as STAT3, AKT and ERK. Poziotinib also induces apoptosis and G1 cell cycle arrest by activating the mitochondrial pathway in HER2 amplified gastric cancer cells. Furthermore, Poziotinib also exerts synergistic effects with chemotherapeutic agents in both HER2 amplified and HER2 non-amplified gastric cancer cells. Kinase Assay: To determine the IC50 values of HM781-36B for kinase inhibition, enzymes of EGFR, HER2, and HER4 are expressed as recombinant proteins in Sf9 insect cells. Enzyme selectivity screening is then performed using a tyrosine kinase assay kit. Briefly, the reactions are performed in 96 well polystyrene round-bottomed plates containing kinase buffer composed of 100 mM HEPES (pH 7.4), 25 mM MgCl2, 10 mM MnCl2 and 250 μM Na3VO4. The reactions are initiated by the addition of 100 ng/assay enzyme, 100 μM ATP, and 10 ng/mL poly(Glu, Tyr). After 1 h of incubation at room temperature, the reactions are terminated by adding 6 mM EDTA solution and then anti-phosphotyrosine antibody, PTK Green Tracer, and FP dilution buffer mixtures. The fluorescence polarization values are then measured after 30 min at room temperature using a Victor3 microplate reader. Finally, the IC50 values were calculated using the following equation: Y = bottom + (top–bottom)/(1 + 10(X-logIC50)). Cell Assay: Viable cell growth is determined by an MTT reduction assay. Briefly, all cell lines (SNU-1, 5, 16, 216, 484, 601, 620, 638, 668, 719, N87 and AGS) are seeded at a density of 3 × 103 per well in 96-well culture plates and then incubated at 37 °C for 24 h. The cells are then treated with 0.001, 0.01, 0.1, or 10 μM of HM781-36B. Three days later, 50 μg of MTT are added to each well and the samples are then incubated for 4 h to reduce the dye. Next, the samples are treated with DMSO, after which the absorbance of the converted dye in the living cells is measured at a wavelength of 540 nm. Six replicate wells are used for each analysis, and at least three independent experiments are conducted. Data points shown represent the mean while bars represent the SE. |
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| In Vivo | In nude mice bearing N87 human gastric cancer xenografts, Poziotinib (0.5 mg/kg p.o.) alone significantly inhibits the growth of tumors, and coadministraion of Poziotinib and 5-FU causes more effective tumor inhibition. In addition, HM781-36B shows excellent antitumor activity in a variety of EGFR- and HER-2-dependent tumor xenograft models, including erlotinib-sensitive HCC827 NSCLC cells, erlotinib-resistant NCI-H1975 NSCLC cells, HER-2 overexpressing Calu-3 NSCLC cells, NCI-N87 gastric cancer cells, SK-Ov3 ovarian cancer cells and EGFR-overexpressing A431 epidermoid carcinoma cancer cells. |
| Animal model | BALB/c athymic nude mice bearing N87 xenografts |
| Formulation & Dosage | Suspended in 23% PEG/TW in water; 0.5 mg/kg; p.o |
| References | Cancer Lett. 2011 Mar 28;302(2):155-65; Int J Cancer. 2012 May 15;130(10):2445-54. |
