1092364-38-9

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Uses

Poziotinib can be used to inhibit the growth of cancer cells.

Synthesis

1429757-65-2

1620740-65-9

1092364-38-9

Bocitinib intermediate 4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-ol (12 g, 34 mmol) and compound (CAS:1620740-65-9) 4-methylbenzenesulfonic acid 1-acryloylpiperidin-4-yl ester (16 g, 51 mmol) were added to K2CO3 prepared in step (1-1) ( 9.4 g, 68 mmol) and dimethylacetamide (DMAc, 300 mL) were mixed. The reaction mixture was heated to 70 °C and stirred at this temperature for 24 hours. Upon completion of the reaction, the mixture was cooled to room temperature and extracted with ethyl acetate (300 mL) followed by washing with water (300 mL). The organic layer was separated and concentrated under reduced pressure. Ethyl acetate was added to the residue to solidify it, and after filtration and drying, the target product 1-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxy-6-quinazolinyl)oxy)-1-piperidinyl)-2-propen-1-one was obtained (12.8 g, Yield: 77%).1H-NMR (300 MHz, DMSO-d6) δ 9.65 (bs, 1H), 8.40 (s, 1H), 7.88 (s, 1H), 7.64-7.56 (m, 2H), 7.24 (s, 1H), 6.89-6.80 (m, 1H), 6.15-6.08 (m, 1H), 5.70-5.66 (m, 1H), 4.78 (m, 1H), 3.94 (s, 3H) , 3.87 (m, 2H), 3.48 (m, 2H), 2.03 (m, 2H), 1.70 (m, 1H).

Enzyme inhibitor

This orally administered, irreversible pan-Human Epidermal growth factor Receptor (HER) inhibitor (FWfree-base = 441.28 g/mol), also known by the code name HM781-36B and systematically as 1-[4-[4- (3,4-dichloro-2- fluorophenylamino) -7-methoxyquinazolin-6-yloxy]-piperidin-1-yl]prop-2- en-1-one hydrochloride, is a new anticancer drug intended to treat advanced solid tumors in clinical trial. HER2-amplified cells were sensitive to HM781-36B (IC50=1-10 nM), arresting in G1 arrest and undergoing subsequent apoptosis. HM781-36B shows promise in the treatment for HER2-amplified breast cancer, especially as a chemosensitizer when used in combination with other cytotoxic agents (e.g., 5-fluorouracil, cisplatin, paclitaxel, or gemcitabine).

storage

Store at -20°C

References

[1] Patent: WO2014/116070, 2014, A1. Location in patent: Page/Page column 10-11

Questions And Answer

• 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.;

• 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.;

• Description

  Poziotinib [1. {4. [4. (3,4. Dichloro.2.monofluoroaniline) -7-methoxyquinazoline-6. Oxygen]. 1. Piperidinyl} propan-2-ene-1one (1)] is a novel oral cancer cell inhibitor developed by Seoul Medical University in South Korea in 2008. It is used for the treatment of breast and gastric cancer, and has targeted Small molecule inhibitor of tyrosine kinase. It is currently in Phase II / III clinical research and can be used alone or in combination for the treatment of gastric, non-small cell lung cancer and breast cancer. Poziotinib is resistant to erlotinib and gefitinib EGFR L858R / T790M Double mutant cells have a strong inhibitory effect.
  The combined use of Poziotinib (HM781-36B) and 5-fluorouracil, platinum compound, paclitaxel or gemcitabine shows a good synergistic inhibitory effect on the overexpression of human epidermis No. 2 (HER2). A new third-generation anti-tumor cell inhibitor following the kinase inhibitor afatinib.

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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.;

• Application

  Poziotinib is suitable for the treatment of patients with advanced NSCLC with exon 20 mutations in EGFR. Multiple patients have proven effective. Poziotinib is also valuable for patients with advanced NSCLC who are resistant to first-generation EGFR TKI and T790M / MET negative. There are no clinical data on the treatment of patients with brain metastases by Poziotinib. One patient with advanced NSCLC with exon 20 mutation in EGFR had meningeal metastases. This patient has been taking Poziotinib for effective control for 4 months.

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