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698387-09-6 (Neratinib)

1

Identification

Neratinib Neratinib
Name Neratinib
Formula C30H29ClN6O3
MW 557.04
CAS No. 698387-09-6
EINECS
Smiles ClC1=C(OCC2=NC=CC=C2)C=CC(NC3=C(C#N)C=NC4=CC(OCC)=C(NC(/C=C/CN(C)C)=O)C=C43)=C1
Synonyms HKI-272;HKI272;HKI 272; (E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide
InChI InChI=1S/C30H29ClN6O3/c1-4-39-28-16-25-23(15-26(28)36-29(38)9-7-13-37(2)3)30(20(17-32)18-34-25)35-21-10-11-27(24(31)14-21)40-19-22-8-5-6-12-33-22/h5-12,14-16,18H,4,13,19H2,1-3H3,(H,34,35)(H,36,38)/b9-7+
2

Introduction

Neratinib (HKI-272) is an orally available, irreversible tyrosine kinase inhibitor with IC50 of 59 nM and 92 nM for HER2 and EGFR, respectively. IC50 value: 59 nM/92 nM (HER2/EGFR) [1] Target: HER2/EGFR in vitro: Neratinib weakly inhibits tyrosine kinases KDR and Src with IC50 of 0.8 μM and 1.4 μM, respectively, being 14- and 24-fold less active compared with HER2.

Background Information

An orally available irreversible tyrosine kinase inhibitor ......by AOBIOUS INC
Neratinib, also known as HKI-272, is considered to be a second-generation inhibitor of the ErbB family of receptor kinases. Sequist, L.V., et al. "Second-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer." Oncologist 12: 325-330 (2007). Neratinib is an irreversible inhibitor of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER-2) tyrosine kinases by targeting a cysteine residue in the ATP-binding site of the receptor. Rabindran, S.K., et al. "Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase." Cancer Res. 64: 3958-3965 (2004). Neratinib inhibits the proliferation of HER-2 overexpressing human breast cancer cell lines and EGFR-dependent cells in vitro. In vivo, neratinib is active against HER-2- and EGFR-dependent tumor xenograft models. Rabindran, S.K., et al. "Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase." Cancer Res. 64: 3958-3965 (2004). Acquired resistance of non-small cell lung cancers to gefitinib because of a T790M mutation in the EGFR kinase domain is circumvented by neratinib. Kwak, E.L., et al. "Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib." Proc. Natl. Acad. Sci. USA 102: 7665-7670 (2005). Neratinib is active against HER-2-positive breast cancer in patients. Wong, K.K., et al. "HKI-272, an irreversible pan erbB receptor tyrosine kinase inhibitor: Preliminary phase 1 results in patients with solid tumors." J. Clin. Oncol. 24: 3018 (2006). Another CAS number previously assigned to neratinib, namely 736156-77-7, has been deleted by CAS and is no longer in use. ......by LC Laboratoies
Neratinib (HKI-272) is an orally available, irreversible tyrosine kinase inhibitor with IC50 of 59 nM and 92 nM for HER2 and EGFR, respectively. IC50 value: 59 nM/92 nM (HER2/EGFR) [1] Target: HER2/EGFR in vitro: Neratinib weakly inhibits tyrosine kinases KDR and Src with IC50 of 0.8 μM and 1.4 μM, respectively, being 14- and 24-fold less active compared with HER2. Neratinib displays no activity against 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, as well as the tyrosine kinase c-Met. Neratinib selectively inhibits the proliferation of 3T3 cells transfected with the HER2 (3T3/neu), as well as two other HER-2-overexpressing SK-Br-3 and BT474 cells with IC50 values of 2-3 nM, displaying >230-fold potency compared with non-transfected 3T3 cells as well as MDA-MB-435 and SW620 which are EGFR- and HER2-negative. Neratinib also inhibits the proliferation of EGFR-dependent A431 cells with an IC50 of 81 nM. Neratinib reduces HER2 receptor autophosphorylation in BT474 cells with an IC50 of 5 nM, and EGF-dependent phosphorylation of EGFR in A431 cells with IC50 of 3 nM. Blocking of HER-2 by Neratinib results in inhibition of downstream MAPK and Akt pathways with IC50 of 2 nM, more potently than Trastuzumab. Neratinib inhibits the cyclin D1 expression and the phosphorylation of the Rb-susceptibility gene production in BT474 cells with IC50 of 9 nM, leading to G1-S arrest and ultimately decreased cell proliferation. in vitro: Oral administration of Neratinib significantly inhibits the growth of 3T3/neu xenografts, with inhibition of 34%, 53%, 98%, and 98% at dose of 10, 20, 40, and 80 mg/kg/day, respectively. Consistent with the inhibition of HER-2 phosphorylation by 84% within 1 hour of administration at 40 mg/kg/day, Neratinib inhibits the growth of BT474 xenografts by 70-82%, 67%, and 93% at dose of 5, 10, and 40 mg/kg/day, respectively. Neratinib is also effective against SK-OV-3 xenografts with inhibition of 31% and 85% at 5 and 60 mg/kg/day, respectively. ......by MedChemexpress Co., Ltd.
Neratinib is an orally available, 6,7-disubstituted-4-anilinoquinoline-3-carbonitrile irreversible inhibitor of the HER-2 receptor tyrosine kinase with potential antineoplastic activity. Neratinib binds to the HER-2 receptor irreversibly, thereby reducing autophosphorylation in cells, apparently by targeting a cysteine residue in the ATP-binding pocket of the receptor. Treatment of cells with this agent results in inhibition of downstream signal transduction events and cell cycle regulatory pathways; arrest at the G1-S (Gap 1/DNA synthesis)-phase transition of the cell division cycle; and ultimately decreased cellular proliferation. Neratinib also inhibits the epidermal growth factor receptor (EGFR) kinase and the proliferation of EGFR-dependent cells. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus) Shelf life: >2 years if stored properly Drug formulation: ......by MedKoo Biosciences, Inc.
Neratinib (HKI-272) is a highly selective HER2 and EGFR inhibitor with IC50 of 59 nM and 92 nM in cell-free assays; weakly inhibits KDR and Src, no significant inhibition to Akt, CDK1/2/4, IKK-2, MK-2, PDK1, c-Raf and c-Met. Phase 3. ......by Selleck Chemicals LLC
Neratinib is an orally available, 6,7-disubstituted-4-anilinoquinoline-3-carbonitrile irreversible inhibitor of the HER-2 receptor tyrosine kinase with potential antineoplastic activity. Neratinib binds to the HER-2 receptor irreversibly, thereby reducing autophosphorylation in cells, apparently by targeting a cysteine residue in the ATP-binding pocket of the receptor. Treatment of cells with this agent results in inhibition of downstream signal transduction events and cell cycle regulatory pathways; arrest at the G1-S (Gap 1/DNA synthesis)-phase transition of the cell division cycle; and ultimately decreased cellular proliferation. Neratinib also inhibits the epidermal growth factor receptor (EGFR) kinase and the proliferation of EGFR-dependent cells. ......by Target Molecule Corp.
3

Protocol(Only for Reference)

Cell Experiment

Cell lines 3T3, 3T3/neu, A431, BT474, SK-Br-3, MDA-MB-435, and SW480
Conditions Dissolved in DMSO, final concentrations 0.5 ng/mL-5 μg/mL; 2 or 6 days
Method Cells are exposed to various concentrations of Neratinib for 2, or 6 days. Cell proliferation is determined using sulforhodamine B, a protein binding dye. Briefly, cells are fixed with 10% trichloroacetic acid and washed extensively with water. Cells are then stained with 0.1% sulforhodamine B and washed in 5% acetic acid. Protein-associated dye is solubilized in 10 mM Tris, and absorbance is measured at 450 nM. The concentration of Neratinib that inhibits cell proliferation by 50% (IC50) is determined from inhibition curves.
Source Selleck Chemicals LLC

Animal Experiment

Animal Models Female athymic (nude) mice implanted s.c. with 3T3/neu, BT474, MCF-7, or SK-OV-3 cells
Dosage ~80 mg/kg/day
Formulation Formulated in 0.5% methocellulose-0.4% polysorbate-80 (Tween 80)
Administration Gavage
Source Selleck Chemicals LLC
4

Physical and Chemical Properties

Appearance:yellow solid EBNumber:EB000029130

Storage condition

Store at or below -20 oC. by LC Laboratoies
4°C by MedChemexpress Co., Ltd.

Solubility

DMSO:< 5.6 mg/mL by CHEMSCENE, LLC
Soluble in DMSO at 2 mg/mL with warming; very poorly soluble in ethanol; very poorly soluble in water; maximum solubility in plain water is estimated to be about 5-20 μM; buffers, serum, or other additives may increase or decrease the aqueous solubility. by LC Laboratoies
DMSO:< 5.6 mg/mL by MedChemexpress Co., Ltd.
(25°C) * In vitro DMSO 2 mg/mL (3.59 mM); Water<1 mg/mL (<1 mM); Ethanol<1 mg/mL (<1 mM); In vivo 30% PEG400+0.5% Tween80+5% Propylene glycol5 mg/mL by Selleck Chemicals LLC
5

Mechanism and Indication

6

Clinical Information

Product Name Sponsor & Collaborators Indications Start Date End Date Phase
Neratinib Puma Biotechnology Inc Metastatic breast cancer 2013/3/31 2018/5/31 Phase 3 Clinical
Neratinib Puma Biotechnology Inc Breast tumor 2009/7/31 2013/10/31 Phase 3 Clinical
Neratinib Puma Biotechnology Inc Solid tumor 2013/9/30 2015/12/31 Phase 2 Clinical
Neratinib Puma Biotechnology Inc Non-small-cell lung cancer 2013/5/31 2016/4/30 Phase 2 Clinical
Neratinib Washington University in St Louis Metastatic breast cancer 2012/12/31 2017/11/30 Phase 2 Clinical
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Safety Data of Neratinib

8

Spectral Information

9

Suppliers List

Company Price and Availability Country/Region
AOBIOUS INC 1mg/USD15() USA
CHEMSCENE, LLC 10mg/USD75(In stock);50mg/USD140(In stock);100mg/USD220(In stock) USA
LC Laboratoies 5mg/USD49(In stock);10mg/USD76(In stock);25mg/USD99(In stock);50mg/USD147(In stock);100mg/USD238(In stock);200mg/USD438(In stock);500mg/USD672(In stock);1g/USD1170(In stock) USA
MedChemexpress Co., Ltd. 5mg/USD50(In stock);10mg/USD75(In stock);50mg/USD140(In stock);100mg/USD220(In stock);200mg/USD290(In stock) USA
MedKoo Biosciences, Inc. USA
Pure Chemistry Scientific Inc. 100mg/USD62(In stock) USA
Selleck Chemicals LLC 5mg/USD150(In stock);10mM/1mLIn DMSO/USD360(In stock);25mg/USD470(In stock);100mg/USD1270(In stock) USA
Shanghai Haoyuan Chemexpress Co., Ltd. 5mg/USD143(In stock);25mg/USD440(In stock);100mg/USD1188(In stock) China
Target Molecule Corp. 2mg/USD96();5mg/USD170();10mg/USD299();50mg/USD850() USA
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Related Products

Other Forms of 698387-09-6

Name CAS No Formula MW
Desmethyl Neratinib 915788-27-1 C29H27ClN6O3 543.02

Recommended Compounds in EGFR

Name CAS No Formula MW
Ginsenoside Rh2 78214-33-2 C36H62O8 622.87
Mutated EGFR-IN-1 1421372-66-8 C25H31N7O 445.56
AZD-9291 (mesylate) 1421373-66-1 C29H37N7O5S 595.71
Mutant EGFR inhibitor 1421373-62-7 C27H30ClN7O2 520.03
AZD-9291 1421373-65-0 C28H33N7O2 499.61
WHI-P180 (hydrochloride) 153437-55-9 C16H16ClN3O3 333.77
WHI-P180 211555-08-7 C16H15N3O3 297.31
Gefitinib (hydrochloride) 184475-55-6 C22H25Cl2FN4O3 483.36
Erlotinib (mesylate) 248594-19-6 C23H27N3O7S 489.54
BGB-102 807640-87-5 C22H25BrN4O2 457.36
Poziotinib 1092364-38-9 C23H21Cl2FN4O3 491.34
CO-1686 (hydrobromide) 1446700-26-0 C27H29BrF3N7O3 636.46
CO-1686 1374640-70-6 C27H28F3N7O3 555.55
CNX-2006 1375465-09-0 C26H27F4N7O2 545.53
PD 168393 194423-15-9 C17H13BrN4O 369.22
AG 18 118409-57-7 C10H6N2O2 186.17
Afatinib (dimaleate) 850140-73-7 C32H33ClFN5O11 718.08
Chrysophanic acid 481-74-3 C15H10O4 254.24
AG-1478 153436-53-4 C16H14ClN3O2 315.75
Mubritinib 366017-09-6 C25H23F3N4O2 468.47

Recommended Compounds in Same Indication

Name CAS No Formula MW
AZD1152 722543-31-9 C26H31FN7O6P 587.54
PU-H71 873436-91-0 C18H21IN6O2S 512.37
BMS-599626 (Hydrochloride) 873837-23-1 C27H28ClFN8O3 567.01
Crizotinib 877399-52-5 C21H22Cl2FN5O 450.34
Ostarine 841205-47-8 C19H14F3N3O3 389.33
AT9283 896466-04-9 C19H23N7O2 381.43
KX2-391 897016-82-9 C26H29N3O3 431.53
Toremifene 89778-26-7 C26H28ClNO 405.96
Toremifene (Citrate) 89778-27-8 C32H36ClNO8 598.08
AT-101 90141-22-3 C30H30O8 518.55
SNX-2112 908112-43-6 C23H27F3N4O3 464.48
Dovitinib 405169-16-6 C21H21FN6O 392.43
MK-0752 471905-41-6 C21H21ClF2O4S 442.9
Nordihydroguaiaretic acid 500-38-9 C18H22O4 302.36
Cyclophosphamide 50-18-0 C7H15Cl2N2O2P 261.09
Pazopanib (Hydrochloride) 635702-64-6 C21H24ClN7O2S 473.98
RX-3117 865838-26-2 C10H12FN3O4 257.22
Fenretinide 65646-68-6 C26H33NO2 391.55
OSU-03012 742112-33-0 C26H19F3N4O 460.45
Retaspimycin 857402-23-4 C31H45N3O8 587.7
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Route of Synthesis

12

References

13

More Information

Neratinib

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