USA Domestic Delivery,Canada Domestic Delivery,European Domestic Delivery

Neratinib

Rating: Category:

Neratinib is a potent, irreversible tyrosine kinase inhibitor (TKI) of HER1, HER2, and HER4, and is currently under development. Neratinib irreversibly binds to the intercellular signaling domain of HER1, HER2, HER3, and epithelial growth factor receptor, and inhibits phosphorylation and several HER downstream signaling pathways. The result is decreased proliferation and increased cell death. Clinical studies have shown that intracellular inhibition of HER signaling by neratinib is a more effective means of suppressing HER-mediated tumor growth and overcoming tumor escape mechanisms experienced with current HER2-targeted therapies and chemotherapeutic agents.

Product Description

Basic Characteristics

Product Name Neratinib
CAS Number 698387-09-6
Molecular Formula C30H29ClN6O3
Formula Weight 557.04
Synonyms HKI-272;

PB272;

Neratinib;

Nerlynx;

698387-09-6.

Appearance Off-white to light yellow powder
Storage and Handling Dry, dark and at 0 – 4 C for short term (days to weeks) or -20 C for long term (months to years).

 

Neratinib 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.

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.

 

Neratinib Mechanism of Action

Neratinib is a potent, irreversible tyrosine kinase inhibitor (TKI) of HER1, HER2, and HER4, and is currently under development. Neratinib irreversibly binds to the intercellular signaling domain of HER1, HER2, HER3, and epithelial growth factor receptor, and inhibits phosphorylation and several HER downstream signaling pathways. The result is decreased proliferation and increased cell death. Clinical studies have shown that intracellular inhibition of HER signaling by neratinib is a more effective means of suppressing HER-mediated tumor growth and overcoming tumor escape mechanisms experienced with current HER2-targeted therapies and chemotherapeutic agents.

Neratinib has also proved to be efficacious in first-line treatment of HER2-positive, metastatic breast cancer (MBC). When used in combination with paclitaxel, neratinib showed an ORR of 73%. When combined with capecitabine, another chemotherapeutic agent, the ORR was 63%. In addition to HER2-positive MBC, neratinib was also efficacious in patients with HER2-mutated breast cancer. In the phase 2 SUMMIT trial, patients with HER2-mutated breast cancer experienced a 33% ORR at 8 weeks.

Neratinib is the first TKI proved to reduce the risk for disease recurrence in patients with early-stage HER2-positive breast cancer. Based on the efficacy of neratinib in early-stage HER2-positive breast cancer, MBC, and HER2-mutant tumors, neratinib is anticipated to become the new standard of care across multiple breast cancer treatment settings.

 

Neratinib Application

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.

HER2-positive breast cancers make too much of the HER2 protein. The HER2 protein sits on the surface of cancer cells and receives signals that tell the cancer to grow and spread. Neratinib fights HER2-positive breast cancer by blocking the cancer cells’ ability to receive growth signals.

Neratinib is a targeted therapy, but unlike Herceptin (chemical name: trastuzumab), Kadcyla (chemical name: T-DM1 or ado-trastuzumab emtansine), and Perjeta (chemical name: pertuzumab), it is not an immune targeted therapy. Immune targeted therapies are versions of naturally occurring antibodies that work like antibodies made by our immune systems. Neratinib is a chemical compound, not an antibody.

 

Neratinib Side Effects & Warning

Neratinib can cause life-threatening diarrhea in some people and mild to moderate diarrhea in almost everyone; people who take it are also at risk for complications of diarrhea like dehydration and electrolyte imbalance.

Similarly there is a risk of severe liver damage and many patients have some level of it; symptoms of liver damage include fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and high levels of eosinophils.

In addition to the above, more than 10% of people taking it have nausea, abdominal pain, vomiting, sores on their lips, stomach upset, decreased appetite, rashes, and muscle spasms.

 

Reference

[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] “Definition of neratinib – National Cancer Institute Drug Dictionary”. Retrieved 1 December 2008.

[9] “Neratinib tablets label” (PDF). U.S. Food and Drug Administration (FDA). July 2017. Retrieved 6 February 2018. For label updates see, FDA index page for NDA 208051 This article incorporates text from this source, which is in the public domain. Gandhi L, et al. (2017). “MA04.02 Neratinib ± Temsirolimus in HER2-mutant lung cancers: an international, randomized phase II study”. Journal of Thoracic Oncology. 12 (1): S358-9. doi:10.1016/j.jtho.2016.11.398.