In Silico Analysis and Molecular Docking Studies of Novel 6,7-dihydropyrano [2,3-d] pyrimidin-5-one Derivatives as Human Epidermal Growth Factor Receptor 2 (HER2) and Epidermal Growth Factor Receptor (EGFR) Inhibitors

Author(s): Ishan I. Panchal*, Ashish Shah, Animesh Devgirkar, Umang Shah, Ashish Patel, Alkesh Patel, Dhrubo J. Sen.

Journal Name: Current Cancer Therapy Reviews

Volume 15 , Issue 3 , 2019

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Abstract:

Background: HER2 is a member of the human epidermal growth factor receptor (HER/EGFR-/ERBB) family. Amplification or over-expression of this oncogene has been shown to play a major role in the development and progression of certain destructive types of breast cancer. Several drugs like Trastuzumab, Pertuzumab, Capecitabine, and Letrozole are used in the patients with metastatic breast cancer that overexpress the HER2 receptor.

Materials and Methods: We aimed to investigate, the prevalence, ADME prediction, biological activity prediction of novel HER2/ EGFR mutations in breast cancer. Literature review shows that pyrano pyrimidin scaffold plays important role in the treatment of Brest cancer. So we have to design novel 6,7-Dihydropyrano [2,3-d] pyrimidin-5-one derivatives with virtual screening techniques. Molecular target prediction shows that all derivatives act on tyrosine kinase.

Results: Among all the compounds H11 (-8.8 kcal/mol), H2 (-8.7 kcal/mol), H15 (-8.6 Kcal/mol), and H17 (-8.7 Kcal/mol) had a maximum binding affinity as compared to Cipecitabine (-6.0 kcal/mol), STD1 (-7.2 Kcal/mol) and STD2 (-7.9 Kcal/mol) and other derivatives. Most of the compounds are moderately active and do not cross the blood brain barrier.

Conclusion: The bioactivity prediction shows that all compounds are active to moderately active. These positive results show that it could be further investigated and explored.

Keywords: HER2, trastuzumab, capecitabine, EGFR, 6, 7-dihydropyrano [2, 3-d] pyrimidin.

[1]
Burstein HJ. The distinctive nature of HER2-positive breast cancers. N Engl J Med 2005; 353(16): 1652-4.
[2]
Santin AD, Bellone S, Roman JJ, McKenney JK, Pecorelli S. Trastuzumab treatment in patients with advanced or recurrent endometrial carcinoma overexpressing HER2/neu. Int J Gynaecol Obstet 2008; 102(2): 128-31.
[3]
Buza N, Roque DM, Santin AD. HER2/neu in endometrial cancer: A promising therapeutic target with diagnostic challenges. Arch Pathol Lab Med 2014; 138(3): 343-50.
[4]
Kaufmann R, Müller P, Hildenbrand G, Hausmann M, Cremer C. Analysis of Her2/neu membrane protein clusters in different types of breast cancer cells using localization microscopy. J Micro 2011; 242(1): 46-54.
[5]
Madarnas Y, Trudeau M, Franek JA, McCready D, Pritchard KI, Messersmith H. Adjuvant/neoadjuvant trastuzumab therapy in women with HER-2/neu-overexpressing breast cancer: A systematic review. Cancer Treat Rev 2008; 34(6): 539-57.
[6]
Mariani G, Fasolo A, De Benedictis E, Gianni L. Trastuzumab as adjuvant systemic therapy for HER2-positive breast cancer. Nat Clin Pract Oncol 2009; 6(2): 93-104.
[7]
Piccart-Gebhart MJ, Procter M, Leyland-Jones B. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005; 353(16): 1659-72.
[8]
Romond EH, Perez EA, Bryant J. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353(16): 1673-84.
[9]
Tomoyasu I, Masaki S, Hiroshi B, et al. Design and synthesis of novel Human Epidermal Growth Factor Receptor 2 (HER2)/Epidermal Growth Factor Receptor (EGFR) dual inhibitors bearing a pyrrolo [3,2-d] pyrimidine scaffold. J Med Chem 2011; 54: 8030-50.
[10]
Li J, Haiyang W, Junjie Li, Jinku B, Chuanfang W. Discovery of a Potential HER2 Inhibitor from natural products for the treatment of HER2-positive breast cancer. Int J Mol Sci 2016; 17: 1055.
[11]
David G, Aurélien G, Matthias W, Antoine D, Olivier M, Vincent Z. Swiss target prediction: A web server for target prediction of bioactive small molecules. Nucleic Acids Res 2014; 42(W1): W32-8.
[13]
Ishan IP, Dhrubo JS, Ashish S, Ashish P, Vashisth B. Molecular docking and synthesis of some substituted Sulphonylurea/Pyrrolidine-based derivatives as hypoglycemic agents. J Chem Pharm Res 2017; 9(8): 164-72.


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Article Details

VOLUME: 15
ISSUE: 3
Year: 2019
Page: [235 - 247]
Pages: 13
DOI: 10.2174/1573394715666181129104528
Price: $65

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