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.
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.
Description
Poziotinib is a TKI that covalently and irreversibly inhibits EGFR and HER2,
and is unique because of its small terminal group and flexible quinazoline core. Its
small size and flexibility allow it to evade the steric hindrance which affects other
EGFR TKIs [138].
Uses
Poziotinib can be used to inhibit the growth of cancer cells.
