Poziotinib (HM781-36B)

Catalog No.S7358 Synonyms: NOV120101

Poziotinib (HM781-36B) Chemical Structure

Molecular Weight(MW): 491.34

Poziotinib (HM781-36B) is an irreversible pan-HER inhibitor with IC50 of 3.2 nM, 5.3 nM and 23.5 nM for HER1, HER2, and HER4, respectively. Phase 2.

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Cited by 1 publication

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Biological Activity

Description Poziotinib (HM781-36B) is an irreversible pan-HER inhibitor with IC50 of 3.2 nM, 5.3 nM and 23.5 nM for HER1, HER2, and HER4, respectively. Phase 2.
Targets
HER1 [1]
(Cell-free assay)		 HER2 [1]
(Cell-free assay)		 HER4 [1]
(Cell-free assay)
3.2 nM 5.3 nM 23.5 nM
In vitro

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. [1]

Assay
Methods Test Index PMID
Western blot
Cleaved caspase-3 / Cleaved caspase-9 / PARP / Bcl-2; 

PubMed: 25761479     


Apoptosis-related proteins were visualized by Western blotting using anti–cleaved caspase-3, anti–cleaved caspse-9, anti–poly(ADP-ribose) polymerase (PARP), and anti–Bcl-2 antibodies. Equal loading was identified by showing the total β-actin levels. The results are representative of two independent experiments (n=2).

pEGFR / EGFR / pHER2 / HER2 / BMX / pERK / ERK / pAKT / AKT ; 

PubMed: 25761479     


Protein expression of the HER family and downstream signaling molecules in colorectal cancer cells following treatment with HM781-36B. Cells were treated with increasing concentrations of HM781-36B (0.001, 0.01, and 0.1 μM) for 48 hours. Cells were lysed, and proteins were analyzed by Western blotting with the indicated antibodies. Results are representative of two independent experiments (n=2). β-Actin was used as a loading control.

25761479
Growth inhibition assay
Cell viability; 

PubMed: 25761479     


The growth inhibitory effect of HM781-36B on a panel of human colorectal carcinoma cell lines. The cells were treated with increasing doses of HM781-36B (0.001-10 μM) for 72 hours. The number of viable cells after the treatment was measured using the luminescent Cell Titer-Glo assay and expressed as percentage viable cells. Data represents the mean±standard error of the mean of three independent experiments (n=3), each of which was replicated six times.

25761479
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. [1] 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. [2]

Protocol

Kinase Assay:[1]
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Enzyme activity 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 Research:[1]
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  • Cell lines: Gastric cancer cell lines (SNU-1, 5, 16, 216, 484, 601, 620, 638, 668, 719, N87 and AGS)
  • Concentrations: ~10 μM
  • Incubation Time: 72 hours
  • Method: Viable cell growth is determined by an MTT reduction assay. Briefly, all cell lines 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.
    (Only for Reference)
Animal Research:[1]
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  • Animal Models: BALB/c athymic nude mice bearing N87 xenografts
  • Formulation: Suspended in 23% PEG/TW in water
  • Dosages: 0.5 mg/kg daily
  • Administration: p.o.
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 98 mg/mL (199.45 mM)
Water Insoluble
Ethanol Insoluble
In vivo Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
2% DMSO+40% PEG 300+2% Tween 80+ddH2O
For best results, use promptly after mixing. 		5mg/mL

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 491.34
Formula

C23H21Cl2FN4O3
CAS No. 1092364-38-9
Storage powder
in solvent
Synonyms NOV120101

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Clinical Trial Information

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT03770988 Not yet recruiting Inoperable or Recurrent or Metastatic Esophageal Squamous Carcinoma Yonsei University April 1 2019 Phase 2
NCT03770988 Not yet recruiting Inoperable or Recurrent or Metastatic Esophageal Squamous Carcinoma Yonsei University April 1 2019 Phase 2
NCT03804515 Not yet recruiting Solid Tumor Spectrum Pharmaceuticals Inc March 2019 Phase 1
NCT03804515 Not yet recruiting Solid Tumor Spectrum Pharmaceuticals Inc March 2019 Phase 1
NCT03744715 Recruiting NSCLC|Breast Cancer Spectrum Pharmaceuticals Inc October 5 2018 Phase 2
NCT03744715 Recruiting NSCLC|Breast Cancer Spectrum Pharmaceuticals Inc October 5 2018 Phase 2

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID