Receptor tyrosine-protein kinase ERCB-2, also known as the CD340 (cluster of differentiation 340), proto-oncogene Neu, Erbb2 (rodent), or ERBB2 (human). Erythroblastic oncogene B is a gene isolated from avian genome, which is commonly called Human Epidermal Growth Factor Receptor 2 (HER2). Over-expression of this oncogene has been shown to play a key role in the enlargement and progression of certain destructive types of breast cancer.
HER2 and cancer
The over-expression of the ERBB2 gene, occurs in about 15-30% of breast cancers (Burstein, 2005). 1 Breast cancer is the most common cancer diagnosed in women, accounting for approximately 23% of all cancer diagnoses and 14% of cancer-related deaths in women universal. Over expression is also known to occur in ovarian, stomach, adenocarcinoma of the lung and aggressive forms of uterine cancer, such as uterine serous endometrial carcinoma (Santin, 2005) 2,3. HER2 is coamplified with the gene GRB7, which is a proto-oncogene connected with breast, testicular embryo cell, gastric, and esophageal lumps. HER2 proteins have been shown to form bunches in cell membranes that may play a role in tumor genesis (Kaufmann, 2011) 4
Current therapy for the breast cancer:
Trastuzumab has become the typical of repair in the dealing with patients with HER2 optimistic breast cancer. The addition of Trastuzumab to chemotherapy schedules in the adjuvant setting progresses concern in women with early stage breast cancer (Madarnas, 2008) 5-8 Pertuzumab is a monoclonal antibody used in the concoction with Trastuzumab and Docetaxel for the dealing of metastatic HER2-positive breast cancer. It’s also used in the same assortment as a neoadjuvant in early HER2-optimistic breast cancer.
HER2 and EGFR, was approved in 2007 in combination with Capecitabine or Letrozole in patients with metastatic breast cancer that overexpress the HER2 receptor. In addition to breast cancer, these HER2/EGFR dual kinase inhibitors are being inspected in a number of solid tumors, like lung, gastric, and prostate cancers. All of these small molecule inhibitors contains a mutual structure categorized by a pyrimidine or pyrimidine analogue at its core. 9 Mechanism of action of Trastuzumab and Pertuzumab is mentioned in Fig.1.
Tomoyasu Ishikawa at. al. has reported substituted Pyrrolo 3,2-d pyrimidine scaffold as Novel HER2 and EGFR dual inhibitors (Tomoyasu, 2011) 9 Jianzong Li et. al has reported the discovery of a potential HER2 inhibitor from ordinary products for the controlling of HER2-positive breast cancer (Jianzong, 2016). 10 From the detailed study of literature review (Tomoyasu, 2011). 9 and 10 we have decided to design novel 6,7-dihydropyrano 2,3-d pyrimidin-5-one derivatives as HER2 inhibitors with the help of molecular modeling. Design of Dihydropyrano 2,3-d pyrimidin-5-one scaffold of innovative HER2/EGFR inhibitor are described in Fig. 2. Design and pharmacokinetic profile of Dihydropyrano 2,3-d pyrimidin-5-one scaffold is mentioned in Fig. 3.
Molecular target prediction:
Bioactive small molecules such as drugs, proteins or other macro-molecular marks to modulate their undertaking, which in turn results in the pragmatic phenotype properties. Drawing the letters of bioactive small molecules is a key step in the direction of unraveling the molecular mechanisms underlying their bioactivity and predicting potential side effects. Recently, large datasets of protein and small molecule interactions have become persisting, providing a unique source of information for the development of knowledge-based tactics to computationally identify new targets for uncharacterized molecules, which are the secondary targets for the molecules. Swiss target prediction, a web server to correctly predict the targets of bioactive molecules based on a combination of 2D and 3D likeness dealings with known ligands. Molecular target of novel derivatives was forecast by Swiss Target Predictor (Gfeller D, 2013) 11 Molecular target prediction of novel selected dihydropyrano 2,3-d pyrimidin-5-one scaffold of HER2/EGFR inhibitors are described in Table 1 for 8.