Neratinib
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MedKoo CAT#: 201470

CAS#: 698387-09-6 (free base)

Description: Neratinib, also known as HKI-272 or PB272, is an orally available, 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.


Chemical Structure

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Neratinib
CAS# 698387-09-6 (free base)

Theoretical Analysis

MedKoo Cat#: 201470
Name: Neratinib
CAS#: 698387-09-6 (free base)
Chemical Formula: C30H29ClN6O3
Exact Mass: 556.19897
Molecular Weight: 557.04
Elemental Analysis: C, 64.68; H, 5.25; Cl, 6.36; N, 15.09; O, 8.62

Price and Availability

Size Price Availability Quantity
25.0mg USD 150.0 Ready to ship
50.0mg USD 250.0 Ready to ship
100.0mg USD 400.0 Ready to ship
200.0mg USD 650.0 Ready to ship
500.0mg USD 1050.0 Ready to ship
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Related CAS #: 698387-09-6 (free base)   915942-22-2 (maleate)    

Synonym: HKI272; HKI 272; HKI-272; PB272; PB 272; PB-272; Neratinib; Nerlynx

IUPAC/Chemical Name: (2E)-N-[4-[[3-chloro-4-[(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide

InChi Key: JWNPDZNEKVCWMY-VQHVLOKHSA-N

InChi Code: 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+

SMILES Code: O=C(NC1=C(OCC)C=C2N=CC(C#N)=C(NC3=CC=C(OCC4=NC=CC=C4)C(Cl)=C3)C2=C1)/C=C/CN(C)C

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Neratinib (HKI-272) is an irreversible tyrosine kinase inhibitor with IC50s of 59 nM and 92 nM for HER2 and EGFR, respectively.
In vitro activity: The efficacy of neratinib in the treatment of HER2 amplified carcinosarcoma was determined in vitro using seven primary carcinosarcoma cell lines with differential expression of HER2/neu. Two of seven (28.5%) carcinosarcoma cell lines were HER2/neu amplified. HER2/neu amplified cell lines SARARK6 and SARARK9 were significantly more sensitive to neratinib than the five non-HER2/neu amplified carcinosarcoma cell lines (mean±SEM IC50: 0.014μM±0.004 vs. 0.164μM±0.019 p=0.0003). Neratinib treatment caused a significant build up in G0/G1 phase of the cell cycle, arrest auto phosphorylation of HER2/neu and activation of S6. Reference: Gynecol Oncol. 2015 Oct;139(1):112-7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4587290/
In vivo activity: Neratinib’s effect in vivo was determined by establishing HER2/neu amplified xenografts of SARARK 6. When subcutaneous tumors reached at least 0.5 cm in a single dimension treatment was initiated. Of the 10 mice injected with SARARK6, a total of nine mice developed subcutaneous tumors. Of the nine mice available, 4 were considered vehicle and 5 were started on neratinib 40mg/kg 5 days weekly by oral gavage. Over the course of 40 days mice tolerated treatment with neratinib well and gained weight at a similar rate compared to vehicle treated controls (data not shown). Treatment with neratinib significantly inhibited tumor growth as early as 9 days after treatment began (p=0.012). Over the course of the treatment period neratinib significantly inhibited tumor growth with the greatest difference noted at 30 days (p<0.0001) as shown in figure 4A. Treatment with neratinib also significantly improved overall survival compared to vehicle treated mice, p=0.0039 (Figure 4B). These data suggest that neratinib is an efficacious treatment for HER2/neu amplified carcinosarcoma in vivo. Reference: Gynecol Oncol. 2015 Oct;139(1):112-7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4587290/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 2.0 3.6

Preparing Stock Solutions

The following data is based on the product molecular weight 557.04 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Ardestani A, Li S, Annamalai K, Lupse B, Geravandi S, Dobrowolski A, Yu S, Zhu S, Baguley TD, Surakattula M, Oetjen J, Hauberg-Lotte L, Herranz R, Awal S, Altenhofen D, Nguyen-Tran V, Joseph S, Schultz PG, Chatterjee AK, Rogers N, Tremblay MS, Shen W, Maedler K. Neratinib protects pancreatic beta cells in diabetes. Nat Commun. 2019 Nov 1;10(1):5015. doi: 10.1038/s41467-019-12880-5. PMID: 31676778; PMCID: PMC6825211. 2. Nagpal A, Redvers RP, Ling X, Ayton S, Fuentes M, Tavancheh E, Diala I, Lalani A, Loi S, David S, Anderson RL, Smith Y, Merino D, Denoyer D, Pouliot N. Neoadjuvant neratinib promotes ferroptosis and inhibits brain metastasis in a novel syngeneic model of spontaneous HER2+ve breast cancer metastasis. Breast Cancer Res. 2019 Aug 13;21(1):94. doi: 10.1186/s13058-019-1177-1. PMID: 31409375; PMCID: PMC6693253.
In vitro protocol: 1. Ardestani A, Li S, Annamalai K, Lupse B, Geravandi S, Dobrowolski A, Yu S, Zhu S, Baguley TD, Surakattula M, Oetjen J, Hauberg-Lotte L, Herranz R, Awal S, Altenhofen D, Nguyen-Tran V, Joseph S, Schultz PG, Chatterjee AK, Rogers N, Tremblay MS, Shen W, Maedler K. Neratinib protects pancreatic beta cells in diabetes. Nat Commun. 2019 Nov 1;10(1):5015. doi: 10.1038/s41467-019-12880-5. PMID: 31676778; PMCID: PMC6825211.
In vivo protocol: 1. Nagpal A, Redvers RP, Ling X, Ayton S, Fuentes M, Tavancheh E, Diala I, Lalani A, Loi S, David S, Anderson RL, Smith Y, Merino D, Denoyer D, Pouliot N. Neoadjuvant neratinib promotes ferroptosis and inhibits brain metastasis in a novel syngeneic model of spontaneous HER2+ve breast cancer metastasis. Breast Cancer Res. 2019 Aug 13;21(1):94. doi: 10.1186/s13058-019-1177-1. PMID: 31409375; PMCID: PMC6693253.

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1: Xuhong JC, Qi XW, Zhang Y, Jiang J. Mechanism, safety and efficacy of three tyrosine kinase inhibitors lapatinib, neratinib and pyrotinib in HER2-positive breast cancer. Am J Cancer Res. 2019 Oct 1;9(10):2103-2119. eCollection 2019. Review. PubMed PMID: 31720077; PubMed Central PMCID: PMC6834479.

2: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Available from http://www.ncbi.nlm.nih.gov/books/NBK548937/ PubMed PMID: 31644242.

3: Booth LA, Roberts JL, Dent P. The role of cell signaling in the crosstalk between autophagy and apoptosis in the regulation of tumor cell survival in response to sorafenib and neratinib. Semin Cancer Biol. 2019 Oct 20. pii: S1044-579X(19)30024-0. doi: 10.1016/j.semcancer.2019.10.013. [Epub ahead of print] Review. PubMed PMID: 31644944.

4: Miles J, White Y. Neratinib for the Treatment of Early-Stage HER2-Positive Breast Cancer. J Adv Pract Oncol. 2018 Nov-Dec;9(7):750-754. Epub 2018 Nov 1. Review. PubMed PMID: 31249722; PubMed Central PMCID: PMC6570523.

5: Collins DM, Conlon NT, Kannan S, Verma CS, Eli LD, Lalani AS, Crown J. Preclinical Characteristics of the Irreversible Pan-HER Kinase Inhibitor Neratinib Compared with Lapatinib: Implications for the Treatment of HER2-Positive and HER2-Mutated Breast Cancer. Cancers (Basel). 2019 May 28;11(6). pii: E737. doi: 10.3390/cancers11060737. Review. PubMed PMID: 31141894; PubMed Central PMCID: PMC6628314.

6: Deeks ED. Neratinib: First Global Approval. Drugs. 2017 Oct;77(15):1695-1704. doi: 10.1007/s40265-017-0811-4. Review. PubMed PMID: 28884417.

7: Kourie HR, El Rassy E, Clatot F, de Azambuja E, Lambertini M. Emerging treatments for HER2-positive early-stage breast cancer: focus on neratinib. Onco Targets Ther. 2017 Jul 10;10:3363-3372. doi: 10.2147/OTT.S122397. eCollection 2017. Review. PubMed PMID: 28744140; PubMed Central PMCID: PMC5513878.

8: Echavarria I, López-Tarruella S, Márquez-Rodas I, Jerez Y, Martin M. Neratinib for the treatment of HER2-positive early stage breast cancer. Expert Rev Anticancer Ther. 2017 Aug;17(8):669-679. doi: 10.1080/14737140.2017.1338954. Epub 2017 Jun 26. Review. PubMed PMID: 28649882.

9: Chan A. Neratinib in HER-2-positive breast cancer: results to date and clinical usefulness. Ther Adv Med Oncol. 2016 Sep;8(5):339-50. doi: 10.1177/1758834016656494. Epub 2016 Jul 10. Review. PubMed PMID: 27583026; PubMed Central PMCID: PMC4981294.

10: Tiwari SR, Mishra P, Abraham J. Neratinib, A Novel HER2-Targeted Tyrosine Kinase Inhibitor. Clin Breast Cancer. 2016 Oct;16(5):344-348. doi: 10.1016/j.clbc.2016.05.016. Epub 2016 May 29. Review. PubMed PMID: 27405796.

11: Kourie HR, Chaix M, Gombos A, Aftimos P, Awada A. Pharmacodynamics, pharmacokinetics and clinical efficacy of neratinib in HER2-positive breast cancer and breast cancer with HER2 mutations. Expert Opin Drug Metab Toxicol. 2016 Aug;12(8):947-57. doi: 10.1080/17425255.2016.1198317. Epub 2016 Jun 27. Review. PubMed PMID: 27284682.

12: Segovia-Mendoza M, González-González ME, Barrera D, Díaz L, García-Becerra R. Efficacy and mechanism of action of the tyrosine kinase inhibitors gefitinib, lapatinib and neratinib in the treatment of HER2-positive breast cancer: preclinical and clinical evidence. Am J Cancer Res. 2015 Aug 15;5(9):2531-61. eCollection 2015. Review. PubMed PMID: 26609467; PubMed Central PMCID: PMC4633889.

13: Feldinger K, Kong A. Profile of neratinib and its potential in the treatment of breast cancer. Breast Cancer (Dove Med Press). 2015 Jun 9;7:147-62. doi: 10.2147/BCTT.S54414. eCollection 2015. Review. PubMed PMID: 26089701; PubMed Central PMCID: PMC4467661.

14: López-Tarruella S, Jerez Y, Márquez-Rodas I, Martín M. Neratinib (HKI-272) in the treatment of breast cancer. Future Oncol. 2012 Jun;8(6):671-81. doi: 10.2217/fon.12.66. Review. PubMed PMID: 22764764.

15: Bose P, Ozer H. Neratinib: an oral, irreversible dual EGFR/HER2 inhibitor for breast and non-small cell lung cancer. Expert Opin Investig Drugs. 2009 Nov;18(11):1735-51. doi: 10.1517/13543780903305428. Review. PubMed PMID: 19780706.



Additional Information

HKI-272 is a potent inhibitor of HER-2 and is highly active against HER-2-overexpressing human breast cancer cell lines in vitro. It also inhibits the epidermal growth factor receptor (EGFR) kinase and the proliferation of EGFR-dependent cells. HKI-272 reduces HER-2 receptor autophosphorylation in cells at doses consistent with inhibition of cell proliferation and functions as an irreversible binding inhibitor, most likely by targeting a cysteine residue in the ATP-binding pocket of the receptor. In agreement with the predicted effects of HER-2 inactivation, HKI-272 treatment of cells results in inhibition of downstream signal transduction events and cell cycle regulatory pathways.