CAS No. : 1092364-38-9

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For research use only. Not Intended for Therapeutic Use!
Cat No:I000381
Molecular Formula:C₂₃H₂₁Cl₂FN₄O₃
Molecular Weight:491.34
IC50:3/5/23 nM(HER1/HER2/HER4)
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Appearance:Solid powder
Purity: > 98%
Cat No:I000381
Cas No:1092364-38-9
IUPAC Name:1-[4-[4-(3,4-dichloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]prop-2-en-1-one

Poziotinib(cas 1092364-38-9) is an irreversible Pan-HER inhibitor with IC50s of 3/5/23 nM for HER1/HER2/HER4 respectively. The IC50 levels of HM781-36B for N87 and SNU216 were 0.001 and 0.004 μmol/L, 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 gefitinib or lapatinib [1]. HM781-36B is a potent inhibitor of EGFR in vitro, including the EGFR-acquired resistance mutation (T790M), as well as HER-2 and HER-4, compared with other EGFR tyrosine kinases inhibitors (erlotinib, lapatinib and BIBW2992). HM781-36B treatment of EGFR DelE746_A750-harboring erlotinib-sensitive HCC827 and EGFR L858R/T790M-harboring erlotinib-resistant NCI-H1975 NSCLC cells results in the inhibition of EGFR phosphorylation and the subsequent deactivation of downstream signaling proteins. 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 M, 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.

1. Cancer Discov. 2018 Jan;8(1):OF4. doi: 10.1158/2159-8290.CD-NB2017-164. Epub 2017 Nov 21.
Poziotinib Shows Promise for Rare Lung Cancer.
Poziotinib, an EGFR inhibitor that was previously shelved as ineffective against non-small cell lung cancer, is showing promising activity in a subset of patients with EGFR exon 20 insertions. According to preliminary data from a phase II trial, the drug led to a 73% overall response rate in patients with this disease subtype, which is typically highly resistant to standard therapy.

2. Cancer Res Treat. 2017 Aug 29. doi: 10.4143/crt.2017.303. [Epub ahead of print]
Phase 1 Studies of Poziotinib, an Irreversible Pan-HER Tyrosine Kinase Inhibitor in Patients with Advanced Solid Tumors.
Kim TM(1)(2)(3), Lee KW(1)(4), Oh DY(1)(2)(3), Lee JS(1)(4), Im SA(1)(2)(3), Kim DW(1)(2)(3), Han SW(1)(2)(3), Kim YJ(1)(4), Kim TY(1)(2)(3), Kim JH(1)(4), Han H(5), Kim WH(6)(2), Bang YJ(1)(2)(3).
Author information:
(1)Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea. (2)Seoul National University Cancer Research Institute, Seoul, Korea. (3)Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea. (4)Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea. (5)Hanmi Pharm. Co., Ltd., Seoul, Korea. (6)Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.
Purpose: Poziotinib, a pan-HER tyrosine kinase inhibitor (TKI), has shown potent activity against wild type of epidermal growth factor receptor (EGFR) family kinases including EGFR, HER-2 and HER-4 and EGFR-mutant cells in vitro. Two phase I studies were conducted to determine the maximum tolerated dose (MTD), pharmacokinetics, safety and antitumor activity against advanced solid tumors. Materials and Methods: Standard 3+3 dose escalation scheme using two different dosing schedules were studied: once daily, 14-day on and 7-day off (intermittent schedule); and once daily continuous dosing with food effect. Additional patients were enrolled in an expansion cohort.
Results: A total of 75 patients were enrolled in the 2 studies. The most common drug-related treatment-emergent adverse events were diarrhea, rash, stomatitis, pruritus, and anorexia. Dose-limiting toxicities were Grade 3 diarrhea in the intermittent schedule and Grade 3 anorexia and diarrhea in the continuous dosing schedule. The MTDs were determined as 24mg/day in the intermittent dosing schedule and 18mg/day in the continuous dosing schedule. Eight (16%) and twenty-four (47%) of 51 evaluable patients in the intermittent schedule achieved partial response (PR) and stable disease (SD), respectively. Four (21%) and six (32%) of 19 evaluable patients in continuous dosing schedule achieved PR and SD, respectively. Patients with PR (n=7) or SD ≥ 12 weeks (n=7) had HER2 amplification (n=7; breast cancer, 5; and stomach cancer, 2) and EGFR amplification (n=1, squamous cell lung cancer).
Conclusions: Poziotinib was safe and well tolerated in patients with advanced solid tumors. It showed an encouraging activity against EGFR-mutant and HER2-amplified cancers.

3. Cancer Res Treat. 2017 Jan;49(1):10-19. doi: 10.4143/crt.2016.058. Epub 2016 May 3.
A Phase II Study of Poziotinib in Patients with Epidermal Growth Factor Receptor (EGFR)-Mutant Lung Adenocarcinoma Who Have Acquired Resistance to EGFR-Tyrosine Kinase Inhibitors.
Han JY(1), Lee KH(2), Kim SW(3), Min YJ(4), Cho E(5), Lee Y(1), Lee SH(1), Kim HY(1), Lee GK(1), Nam BH(1), Han H(6), Jung J(6), Lee JS(1).
Author information:
(1)Center for Lung Cancer, National Cancer Center, Goyang, Korea. (2)Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Korea. (3)Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. (4)Department of Internal Medicine, Ulsan University Hospital, Ulsan, Korea. (5)Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea. (6)Clinical Research Team, Hanmi Pharmaceutical Co., Ltd., Seoul, Korea.
PURPOSE: We examined the efficacy of poziotinib, a second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) in patients with lung adenocarcinoma with activating EGFR mutations, who developed acquired resistance (AR) to EGFR-TKIs.
MATERIALS AND METHODS: This single-arm phase II study included EGFR-mutant lung adenocarcinoma with AR to erlotinib or gefitinib based on the Jackman criteria. Patients received poziotinib 16 mg orally once daily in a 28-day cycle. The primary endpoint was progression-free survival (PFS). Prestudy tumor biopsies and blood samples were obtained to determine resistance mechanisms.
RESULTS: Thirty-nine patients were treated. Tumor genotyping was determined in 37 patients; 19 EGFR T790M mutations and two PIK3CA mutations were detected in the prestudy tumors, and seven T790M mutations were detected in the plasma assay. Three (8%; 95% confidence interval [CI], 2 to 21) and 17 (44%; 95% CI, 28 to 60) patients had partial response and stable disease, respectively. The median PFS and overall survival were 2.7 months (95% CI, 1.8 to 3.7) and 15.0 months (95% CI, 9.5 to not estimable), respectively. A longer PFS was observed for patients without T790M or PIK3CA mutations in tumor or plasma compared to those with these mutations (5.5 months vs. 1.8 months, p=0.003). The most frequent grade 3 adverse events were rash (59%), mucosal inflammation (26%), and stomatitis (18%). Most patients required one (n=15) or two (n=15) dose reductions.
CONCLUSION: Low activity of poziotinib was detected in patients with EGFR-mutant non-small cell lung cancer who developed AR to gefitinib or erlotinib, potentially because of severe-toxicityimposed dose limitation.

4. Cancer Chemother Pharmacol. 2015 Jan;75(1):97-109. doi: 10.1007/s00280-014-2621-7. Epub 2014 Nov 7.
Population pharmacokinetics of HM781-36 (poziotinib), pan-human EGF receptor (HER) inhibitor, and its two metabolites in patients with advanced solid malignancies.
Noh YH(1), Lim HS, Jung JA, Song TH, Bae KS.
Author information:
(1)Department of Clinical Pharmacology, Busan Paik Hospital, Inje University, Busan, Korea.
PURPOSE: To develop a population pharmacokinetic (PK) model for HM781-36 (poziotinib) and its metabolites in cancer patients. METHODS: Blood samples were collected from three phase I studies in which fifty-two patients received oral HM781-36B tablets (0.5-32 mg) once daily for 2 weeks, and another 20 patients received oral HM781-36B tablets (12, 16, 18, 24 mg) in fasting (12 patients) or fed (eight patients) state once daily for 4 weeks. Nonlinear mixed effect modeling was employed to develop the population pharmacokinetic model.
RESULTS: HM781-36 PK was ascribed to a two-compartment model and HM781-36-M1/-M2 PK to one-compartment model. HM781-36 oral absorption was characterized by first-order input (absorption rate constant: 1.45 ± 0.23 h⁻¹). The central volume of distribution (185 ± 12.7 L) was influenced significantly by body weight. The absorption rate constant was influenced by food. The typical HM781-36 apparent clearance was 34.5 L/h (29.4 %CV), with an apparent peripheral volume of distribution of 164 L (53.5 %CV). Other covariates did not significantly further explain the PKs of HM781-36.
CONCLUSIONS: The proposed model suggests that HM781-36 PKs are consistent across most solid tumor types, and that the absorption process of HM781-36 is affected by the fed state before dosing. HM781-36 PKs are not complicated by patient factors, other than body weight.
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