Novel Molecule of Protein Tyrosine Kinase Enzyme Inhibitor in Treatment of Breast Cancer: Neratinib Maleate

 

Sandip S. Kshirsager¹*, Dr. Siraj N. Shaikh¹, Narendra B. Patil², Ketan B. Patil²

 

¹Department of Pharmaceutics, Ali Allana College of Pharmacy, Akkalkuwa, Maharashtra

²Department of Pharmacology, Ahinsa Institute of Pharmacy, Dondaicha, Dist-Dhule, Maharashtra

 

ABSTRACT:

Cancer is leading cause of death worldwide, accounting for an estimated 9.6 million deaths in 2018.Breast cancer 2.09 million death in 2018. Approximately 70% of deaths from cancer occurs in low- and middle-income countries. Human epidermal growth factor receptor (HER) 2 is overexpressed in 20 -25% of breast cancer and has historically been poor prognostics marker. Niratinib maleate is an anti breast cancer drug .it is crystalline form and chemically (2E)-N-[4-[[3-chloro-4-[(pyridin-2-yl) methoxy] phenyl] amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino) but-2-enamide maleate. It an oral, irreversible pan-Erb B receptor tyrosine kinase inhibitor and it can effectively inhibit the activity of Erb B1, ErbB2 tyrosine kinase.

 

 

 

INTRODUCTION:

Cancer is a major public health problem worldwide and cancer is the second leading cause of death globally.its estimated 9.6 million deaths in 2018, globally about 1 in 6 deaths due to cancer. Approximately 70% of death from cancer occour in low and middle countries, breast cancer 2.09 million death in 2018. (1)

 

Cancer remains the most serious disease that threatens human health molecularly targeted cancer therapies, specifically small molecule tyrosine kinase inhibitor from an important part of cancer therapy. (2).

 

Human epidermal growth factor receptor (HER) 2 is overexpressed in 20-25% of breast cancer, has historically been a poor prognostic marker. (3)

 

Neratinib maleate is an anti breast cancer drug and it an oral, irrversible pan-Erb B receptor tyrosine kinase inhibitor.it is can effectively inhibit the activity of Erb B1 and Erb B2 tyrosine kinase. (4)

 

Table no. 1 Patent details of Niratinib maleate. (4)

Applicant	Crystal Pharmatech Co., Ltd., Suzhou, Jinangsu (CN).
Inventors	1. Minhua Chen, Suzhou, Jiangsu (CN) 2. Xiaojuan Diao, Suchou, (CN). 3. Xiaoyu Zhang, Suzhou (CN) 4. Yanfeng Zhang, Suzhou (CN)
Assignee	Crystal Pharmatech Co, Ltd., Suzhou, Jinangsu (CN).
Application no.	15/542,597
PCT filed	Jan.8,2016
PCT no.	PCT/ CN2016/070472
Publication no.	Us 2018/0265495A1
Publication date	Sep. 20,2018

 

Chemistry of Niratinib Maleate:

The novel crystalline form of niratinib maleate is 6,7 - disubstituted-4-anilinoquinoline-3-carbonitrile derivatives and chemical name is (2E)-N-[4-[[3-chloro-4- [(pyridin-2-yl) methoxy]phenyl] amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide maleate.molecuar formula is C30 H29 Cl N6O3. C4H4O4. its molecular weight is 673.11g/mol. It is off white to yellow powder and solubility in aqueous media. (5)

 

Mechanism of action:

Niratinib maleate binds to and irreversibly inhibits EFGR, HER2 and HER4, this prevents autophosphorylation of tyrosine residues on the receptor and reducing signaling through the mitogen-activated protein kinase pathways. (5)

 

Dosage form and Doses:

Absorption of neratinib maleate is gastrointestinal tract .apperant volume of distribution at steady state is 6433 L and elimination 97.1% of the total is excreted in feces and 1.13% in the urine.it is mainly undergoes metabolism via CYP3P4.the half life of elimination ranges from 7-17 hr of single dose.protein binding 99 % bind to human plasma proteins.it binds both Human serum albumin and α-1 acid glycoprotein.(5)

 

Adverse effect:

Its causes diarrhea and most of other gastrointestinal complications (7) dehydration and electrolyte imbalance, severe liver damage, fatigue, nausea, alopecia, right quadrant pain, high levels of eosinophills. (8)

 

Contraindications:

It can cause fetal harm when administered to a pregnant woman, severally of diarrhoea, hepatotoxicity. (9)

 

HER Pathway in Breast Cancer:

The family of HER (or ERBB) receptors is composed of four members, HER1 (EGFR, ERBB1), HER2 (ERBB2, HER2/neu), HER3 (ERBB3) and HER4 (ERBB4) (10), all of which have a function in controlling cell growth, proliferation, and survival. Structurally, each of them is located at the cell membrane and consists of two cysteine-rich extracellular ligandbinding domains, a single transmembrane domain and, with the exception of HER3, an intracellular tyrosine kinase domain. Binding with ligands induces conformational changes in HER1, HER3 and HER4 (11) causing them to dimerize with either themselves (homodimerization) or other HER receptors (heterodimerization) and undergo phosphorylation of the tyrosine kinase (12). This results in activation of several downstream intracellular signaling pathways that mediate cell growth and proliferation, of which the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR)/Akt and mitogenactivated protein kinase (MAPK) pathways are the most important (13-15). Several mechanisms can lead to aberrant hyperactivation of HER receptors, including overexpression and somatic mutations resulting in constitutive activation. HER2 is the most frequently altered gene of the HER family, and approximately 15% to 20% of all breast cancers have HER2 gene amplification or overexpression (10).it is constitutively in an open conformation ready for dimerization (16) and is the preferred partner for heterodimerization of the other HER receptors (17). HER2 heterodimers (e.g. HER2/HER3) are more effective than HER2 homodimers in promoting carcinogenesis through activation of intracellular signaling pathways (18,19). Sequencing studies have demonstrated that HER2 can also be affected by somatic mutations in HER2 non-amplified breast cancers (20,21). These are thought to occur in approximately 2% of primary breast cancers (22) although, the frequency of HER2 mutations in relapsed or metastatic breast cancers is currently unknown (21).Many of these mutations are activating events leading to oncogenic transformation (21), and some mutations have been associated with a lack of response to HER2-directed treatments in the metastatic setting (23).

 

Fig.no. 1 HER Pathway in Breast Cancer

 

CONCLUSION:

One of the major break throughs of breast cancer treatment for the part decade is the development of HER 2 targeted therapies. niratinib maleate is apotent orally available, pan -HER inhibitor with HER 2 amplified and HER 2 mutated Breast cancer. Niratinib maleate is tyrosine kinase inhibitor.it all information is useful to the analytical research and bioanalytical researcher for study of the niratinib maleate.

 

CONFLICT OF INTREST:

None.

 

REFERENCE:

1.      https:// www.who.org.

2.      Luhong Wang, Jingyuan Zhao, Changyuanwang, Jianbin Zhang, Hing Yuan, Covalent binding design therapy: A prospective method for discovery of potent targeted anticancer agents; European Journal of medicinal chemistry,2017,9(24),1-34.

3.      Xiaosongzhang, Pamela N. Munster, New protein kinase inhibitors in Breaet cancer: fatinib, Neratinib, Expert opin. Pharmacother. 2014,15(9),1277-1288.

4.      Minhua Chen, Yanfeng Zhang, Xiaojuan Diao, Xiaoyuzhang; New crystal form of nratinib maleate, United states patent application publication, 2018,1-10.

5.      https://Pubchem.ncbi.nim.nih.gov

6.      https://www.drugbank.ca/ drugs.

7.      Nan Jiang, Xiang –wei song, Ao Li, Cheng –Lin Li, Yan Cui, Riskm of gastrointestinal complication in breast cancer patients treated with neratinib,: a meta analysis,Expert opinion of drug safety,2017,1-9.

8.      https:// en.mwikipedia.org.

9.      https://reference.medscape.com

10.   Baselga J, Swain SM. Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nat Rev Cancer 2009; 9:463-75

11.   Linggi B, Carpenter G. ErbB receptors: new insights on mechanisms and biology. Trends Cell Biol 2006; 16:649-56

12.   Zhang X, Gureasko J, Shen K, et al. An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell 2006; 125:1137-49

13.   Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. NatRev Cancer 2002; 2:489-501

14.   Dankort D, Maslikowski B, Warner N, et al. Grb2 and Shc adapter proteins play distinct roles in Neu (ErbB-2)-induced mammary tumorigenesis: implications for human breast cancer. Mol Cell Biol 2001; 21:1540-51

15.   Moasser MM. The oncogene HER2: it signaling and transforming functions and its role in human cancer pathogenesis. Oncogene 2007; 26:6469-87

16.   Cho HS, Mason K, Ramyar KX, et al. Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature 2003; 421:756-60

17.   Graus-Porta D, Beerli RR, Daly JM, et al. ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J 1997; 16:1647-55

18.   Nahta R, Esteva FJ. Herceptin: mechanisms of action and resistance. Cancer Lett 2006; 232:123-38

19.   Way TD, Lin JK. Role of HER2/HER3 co-receptor in breast carcinogenesis. Future Oncol 2005; 1:841-9

20.   Lee JW, Soung YH, Seo SH, et al. Somatic mutations of ERBB2 kinase domain in gastric, colorectal, and breast carcinomas. Clin Cancer Res 2006; 12:57-61

21.   Bose R, Kavuri SM, Searleman AC, et al. Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov 2013; 3:224-37

22.   Study which assesses the in vitro activity of neratinib in HER2 mutations in breast cancer.

23.   Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 2012; 490:61–70

24.   Boulbes DR, Arold ST, Chauhan GB, et al. HER family kinase domain mutations promote tumor progression and can predict response to treatment in human breast cancer. Mol Oncol 2015; 9: 586-600.

 

 

Accepted on 29.03.2020      ©Asian Pharma Press All Right Reserved