来那替尼,(2E)-N-[4-[[3-氯-4-[(吡啶-2-基)甲氧基]苯基]氨基]-3-氰基-7-乙氧基喹啉-6-基]-4-(二甲基氨基)丁-2-烯酰胺
Neratinib
CAS: 698387-09-6
Molecular Formula: C30H29ClN6O3
来那替尼,(2E)-N-[4-[[3-氯-4-[(吡啶-2-基)甲氧基]苯基]氨基]-3-氰基-7-乙氧基喹啉-6-基]-4-(二甲基氨基)丁-2-烯酰胺 - Names and Identifiers
来那替尼,(2E)-N-[4-[[3-氯-4-[(吡啶-2-基)甲氧基]苯基]氨基]-3-氰基-7-乙氧基喹啉-6-基]-4-(二甲基氨基)丁-2-烯酰胺 - Physico-chemical Properties
| Molecular Formula | C30H29ClN6O3 |
| Molar Mass | 557.04 |
| Density | 1.33 |
| Melting Point | 185-187°C |
| Boling Point | 757.0±60.0 °C(Predicted) |
| Flash Point | 411.601°C |
| Solubility | Soluble in DMSO (2 mg/ml at 25 °C), water (<1 mg/ml at 25 °C), and ethanol (<1 mg/m |
| Vapor Presure | 0mmHg at 25°C |
| Appearance | Off-white solid. |
| Color | Pale Yellow to Yellow |
| pKa | 12.37±0.43(Predicted) |
| Storage Condition | Refrigerator |
| Refractive Index | 1.667 |
| Use | A potent and selective inhibitor of EGFR and HER2 |
| In vitro study | Neratinib weakly inhibited the tyrosine kinases KDR and Src with IC50 of 0.8 μm and 1.4 μm, respectively, and the activity was 14 and 24 times weaker than that of HER-2, respectively. Neratinib acts on other serine-threonine kinases such as Akt, cyclin D1/cdk4, cyclin E/cdk2, cyclin B1/cdk1, IKK-2, MK-2, PDK1, c-Raf, and Tpl-2, and tyrosine kinase c-Met is not active. Neratinib selectively inhibits proliferation of 3T3 cells transfected with HER-2 (3T3/neu) and also inhibits proliferation of two other HER-2-overexpressing SK-Br-3 and BT474 cells, the IC50 was 2-3 nM, which was more than 230-fold higher than that of untransfected 3T3 cells and EGFR-and HER-2 negative MDA-MB-435 and SW620 cells. Neratinib also inhibited EGFR-dependent A431 cell proliferation with an IC50 of 81 nM. Neratinib acts on BT474 cells to reduce HER-2 receptor autophosphorylation with IC50 of 5 nM, and acts on A431 cells to reduce EGF-dependent phosphorylation of EGFR with IC50 of 3 nM. Neratinib inhibits HER-2, resulting in inhibition of the downstream MAPK and Akt pathways with an IC50 of 2 nM, which is more potent than Trastuzumab. Neratinib acts on BT474 cells to inhibit the expression of cyclin D1 and the phosphorylation of Rb-sensitive gene products with an IC50 of 9 nM, resulting in a cell cycle stop at phase G1-S, which ultimately reduces cell proliferation. |
| In vivo study | Oral treatment with Neratinib at doses of 10, 20, 40, and 80 mg/kg per day significantly inhibited the growth of 3T3/neu Xenografts by 34%, 53%, 98%, and 98%, respectively. Neratinib inhibited HER-2 phosphorylation by 84% within 1 hour at a dose of 40 mg/kg daily, and correspondingly, Neratinib treated BT474 xenografts at doses of 5, 10, and 40 mg/kg daily, inhibition was 70-82%, 67%, and 93%, respectively. Neratinib was also effective in the SK-OV-3 xenograft, with 31% and 85% inhibition at 5 and 60 mg/kg daily. Neratinib was less effective in EGFR-dependent A431 xenografts than in HER-2-dependent tumors, with 32% and 44% inhibition at 5 and 20 mg/kg daily. Neratinib showed little activity in MCF-7 and MX-1 transplanted tumors expressing low levels of HER-2 and EGFR, and the inhibition was only 28% at a dose of 80 mg/kg per day, it is indicated that Neratinib acts selectively on cells expressing HER-2 or EGFR. |
来那替尼,(2E)-N-[4-[[3-氯-4-[(吡啶-2-基)甲氧基]苯基]氨基]-3-氰基-7-乙氧基喹啉-6-基]-4-(二甲基氨基)丁-2-烯酰胺 - Risk and Safety
| HS Code | 29334900 |
来那替尼,(2E)-N-[4-[[3-氯-4-[(吡啶-2-基)甲氧基]苯基]氨基]-3-氰基-7-乙氧基喹啉-6-基]-4-(二甲基氨基)丁-2-烯酰胺 - Introduction
Neratinib (HKI-272) is a highly selective HER2 and EGFR inhibitor with IC50 of 59 nM and 92 nM respectively. Weak inhibition of KDR and Src did not significantly inhibit Akt,CDK1/2/4, IKK-2, MK-2, PDK1, c-Raf and c-Met. Phase 3.
Last Update：2022-10-16 17:28:01
来那替尼,(2E)-N-[4-[[3-氯-4-[(吡啶-2-基)甲氧基]苯基]氨基]-3-氰基-7-乙氧基喹啉-6-基]-4-(二甲基氨基)丁-2-烯酰胺 - Reference Information
| new anti-cancer drug | Lenatinib is an irreversible epidermal growth factor receptor (EGFR) developed by Wyeth in the United States Inhibitor. It is a small molecule tyrosine kinase inhibitor targeting HER2 and HER1 after lapatinib. It is an irreversible pan-ErbB receptor tyrosine kinase inhibitor. It can selectively inhibit HER-1 and HER-2 in EGFR family (IC50 is 92nmol/L and 59nmol/L respectively). Clinical studies have shown that it has obvious therapeutic effects on non-small cell lung cancer, colon cancer, and breast cancer. Phase II clinical trials have shown that renatinib has good efficacy and tolerance for advanced HER-2 positive breast cancer patients treated with or without trastuzumab. Phase III clinical study of breast cancer completed in September 2014. The data show that in the treatment of early HER-2 positive breast cancer, lenatinib is more effective than Herceptin (Herceptin) of Roche. |
| Introduction | Lenatinib is a tyrosine kinase inhibitor. On July 17, 2017, FDA approved it for prolonged adjuvant therapy (extendedadjuvanttherapy) for early HER2-positive breast cancer. For this type of cancer, Lenatinib is the first prolonged adjuvant treatment. |
| Synthesis | Using 3-chloro-4-(pyridine-2-methoxy)-aniline (2) and N-(4-chloro-3-cyano-7-ethoxyquinoline-6-yl)-acetamide (3) as raw materials, N-[4-[3-chloro-4-(pyridine-2-methoxy) anilino]-3-cyano-7-ethoxyquinoline-6-yl] acetamide (4),4 is deprotected under the action of hydrochloric acid, then the free base is precipitated in the methanol solution of potassium carbonate to prepare 3-cyano-6-amino-4-[3-chloro-4-(pyridine-2-methoxy) anilinyl]-7-ethoxyquinoline (5),5 is condensed with the acid chloride prepared by the Vilsmeier reaction of trans-4-dimethylaminocrotonic acid hydrochloride (6) to prepare natinib (1). Fig. 1 shows the synthetic route of lenatinib |
| side effects | are diarrhea, nausea, vomiting and fatigue. The new anti-cancer drug, synthesis, and side effects of Lai Natinib are edited by Shi Yan. (2015-10-23) |
| biological activity | Neratinib (HKI-272) is a highly selective HER2 and EGFR inhibitor with IC50 of 59 nM and 92 nM respectively in cell-free test. Weak inhibition of KDR and Src, for Akt,CDK1/2/4,IKK-2,MK-2,PDK1,c-Raf and c-Met did not significantly inhibit. Phase 3. |
| target | TargetValue her2 (cell-free assay) 59 nmEGFR (cell-free assay) 92 nmkdr (cell-free assay) 800 nmsrc (cell-free assay) 1.4 μ m |
| Target | Value |
| HER2 (Cell-free assay) | 59 nM |
| EGFR (Cell-free assay) | 92 nM |
| KDR (Cell-free assay) | 800 nM |
| Src (Cell-free assay) | 1.4 μM |
| in vitro study | Neratinib weakly inhibit tyrosine kinases KDR and Src,IC50 is 0.8 μM and 1.4 μM respectively, compared with HER-2, the activity is 14 and 24 times weaker respectively. Neratinib acting on other serine-threonine kinases such as Akt, cyclin D1/cdk4, cyclin E/cdk2, cyclin B1/cdk1, IKK-2, MK-2, PDK1, c-Raf, and Tpl-2, and tyrosine kinase c-Met have no activity. Neratinib selectively inhibited the proliferation of 3T3 cells transfected with HER-2 (3T3/neu), and also inhibited the proliferation of two other HER-2-overexpressing SK-Br-3 and BT474 cells with an IC50 of 2-3 nM, which was more than 230-fold higher than that of untransfected 3T3 cells and EGFR-and HER-2 negative MDA-MB-435 and SW620 cells. Neratinib also inhibited the proliferation of EGFR-dependent A431 cells with an IC50 of 81 nM. Neratinib acts on BT474 cells, reduces HER-2 receptor autophosphorylation, IC50 is 5 nM, acts on A431 cells, reduces EGF-dependent EGFR phosphorylation, IC50 is 3 nM. Neratinib inhibition of HER-2 leads to inhibition of downstream MAPK and Akt pathways with IC50 of 2 nM, which is more effective than Trastuzumab. Neratinib acts on BT474 cells to inhibit cyclin D1 expression and phosphorylation of Rb-sensitive gene products. IC50 is 9 nM, resulting in cell cycle stopping at G1-S phase and eventually reducing cell proliferation. |
| in vivo study | Neratinib were orally treated at doses of 10, 20, 40, and 80 mg/kg daily to give 3T3/neu transplanted tumor, significantly inhibiting growth, inhibiting 34%, 53%, 98%, and 98% respectively. The Neratinib was treated at a dose of 40 mg/kg per day, and 84% HER-2 phosphorylation was inhibited within 1 hour. Accordingly, the Neratinib treated BT474 transplanted tumor at doses of 5, 10, and 40 mg/kg per day, with inhibition of 70-82%, 67%, and 93%, respectively. Neratinib is also effective in SK-OV-3 transplanted tumors, treated at doses of 5 and 60 mg/kg per day, with inhibition of 31% and 85% respectively. The effect of Neratinib on EGFR-dependent A431 transplanted tumor is weaker than that on HER-2-dependent tumor, and the inhibition is 32% and 44% respectively when treated at doses of 5 and 20 mg/kg per day. Neratinib has little activity on MCF-7 and MX-1 transplanted tumors expressing low levels of HER-2 and EGFR, and the inhibition is only 28% treated at a dose of 80 mg/kg per day, indicating that Neratinib selectively acts on cells expressing HER-2 or EGFR. |
Last Update：2024-04-09 21:04:16
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来那替尼,(2E)-N-[4-[[3-氯-4-[(吡啶-2-基)甲氧基]苯基]氨基]-3-氰基-7-乙氧基喹啉-6-基]-4-(二甲基氨基)丁-2-烯酰胺
G蛋白偶联受体激酶相互作用ArfGAP蛋白2
酸性蓝3号钠盐,酸性蓝3号
2,5-二氯噻唑-4-羧酸乙酯
N6-[4-[(1E)-2-[4-(二甲氨基)苯基]偶氮基]苯甲酰基]-N2-[(9H-芴-9-基甲氧基)羰基]-L-赖氨酸
甲基-beta-D-呋喃核糖苷
4-Aminobenzoic acid hydrochloride
G蛋白偶联受体激酶相互作用ArfGAP蛋白2
酸性蓝3号钠盐,酸性蓝3号
2,5-二氯噻唑-4-羧酸乙酯
N6-[4-[(1E)-2-[4-(二甲氨基)苯基]偶氮基]苯甲酰基]-N2-[(9H-芴-9-基甲氧基)羰基]-L-赖氨酸
甲基-beta-D-呋喃核糖苷
4-Aminobenzoic acid hydrochloride