A Review on Fused Pyrimidine Systems as EGFR Inhibitors and Their Structure–Activity Relationship

Abstract

Epidermal growth factor receptor (EGFR) belongs to the family of tyrosine kinase that is activated when a specific ligand binds to it. The EGFR plays a vital role in the cellular proliferation process, differentiation, and apoptosis. In the case of cancer, EGFR undergoes uncontrolled auto-phosphorylation that results in increased cellular proliferation and decreased apoptosis, causing cancer promotion. From the literature, it shows that pyrimidine is one of the most commonly studied heterocycles for its antiproliferative activity against EGFR inhibition. The authors have collated some interesting results in the heterocycle-fused pyrimidines that have been studied using different cell lines (sensitive and mutational) and in animal models to determine their activity and potency. It is quite clear that the fused systems are highly effective in inhibiting EGFR activity in cancer cells. Therefore, the structure–activity relationship (SAR) comes into play in determining the nature of the heterocycle and the substituents that are responsible for the increased activity and toxicity. Understanding the SAR of heterocycle-fused pyrimidines will help in getting a better overview of the molecules concerning their activity and potency profile as future EGFR inhibitors.

Development of Furanopyrimidine-Based Orally Active Third-Generation EGFR Inhibitors for the Treatment of Non-Small Cell Lung Cancer

“…As the incorporation of a solubilizing functional group in compounds 31 and 32 lowered its EGFR kinase inhibition activity and failed to impart cellular potency, we used molecular docking studies to identify a site capable of bearing a solubilizing group without that group also affecting the EGFR kinase enzyme inhibitory activity. Osimertinib (6) was docked onto the crystal structure of DBPR112 (11) and their binding orientation in the EGFR protein was compared (Figure 2). It was found that the Michael acceptor group of 6 was placed near the Cys797 residue, similar to 11.…”

“…Lung cancer is one of the leading causes of cancer deaths worldwide, accounting for a quarter of all cancer deaths. , Most lung cancer patients, around 80–85%, have the non-small cell lung cancer (NSCLC) disease, which is characterized by somatic epidermal growth factor receptor (EGFR) activating mutations in 10–15% of Caucasian and 30–50% of Asian patients. , Several drugs targeting mutated EGFR have been approved, such as the first-generation EGFR inhibitors gefitinib ( 1 ) and erlotinib ( 2 ), which were approved by the US FDA in 2003 and 2004 (Figure ). − Gefitinib and erlotinib effectively target the EGFR exon 19 deletion or exon 21 L858R single point mutation , and most patients respond well, but about half of them develop resistance due to a secondary T790M gatekeeper mutation. , Several second-generation EGFR inhibitors capable of overcoming resistance due to T790M mutations have also been approved, including afatinib ( 3 ), dacomitinib ( 4 ), and ceritinib ( 5 ). These second-generation inhibitors all bear a Michael acceptor warhead that forms an irreversible covalent bond with the cysteine residue (Cys797) in the active site of EGFR …”

“….8, 1.2 Hz, 1H),6.53 (dd, J = 17.4, 10.2 Hz, 1H), 6.27 (dd, J = 17.4, 2.1 Hz, 1H), 5.89 (t, J = 6.0 Hz, 1H), 5.77 (dd, J = 10.2, 2.1 Hz, 1H), 3.73 (s, 2H), 3.11 (s, 2H), 2.64 (s, 6H) 13. C NMR (150 MHz, DMSO-d 6 ) δ 164.7, 163.5, 157.1, 153.8, 146.0, 140.1, 131.7, 131.4, 130.2, 128.9, 128.82, 128.81, 127.2, 126.2, 124.8, 120.2, 119.7, 115.3, 102.5, 55.8, 42.8, 40.0, 36.2.…”

Necrotizing apoptosis‐related genes prognosis and treatment effect analysis of osteosarcoma in children

“…In the present research, we studied the relationship between Among all of the identified genes, the EGFR belongs to a family of tyrosine kinases that are activated when specific ligands bind to them. 29,30 EGFR plays a crucial role in the cell proliferation process, differentiation and apoptosis. 30 In the case of cancer, EGFR undergoes uncontrolled autophosphorylation, leading to increased cell proliferation and decreased apoptosis, which results in cancer promotion.…”

Regioselective synthesis of fused pyrimidines and quinazolines linked to Phenoxy‐N‐arylacetamide moieties as novel hybrid molecules via Biginelli‐like reaction

“…Pyrimidine and its fused derivatives are a class of heterocyclic scaffolds with biological and pharmacological activities [16][17][18][19][20][21][22][23][24][25] including anticancer [16][17][18], antihypertensive [19], anxiolytic, antioxidant [16], antiviral, antifungal [20][21][22], anti-inflammatory [23], analgesic activities [23], and antibacterial [21,22] properties. These compounds hold a unique place in the field of biological and medicinal chemistry, inspiring researchers to create novel motifs with modified structures [26,27]. In the framework of our current research interest in carboncarbon bond-forming reactions [28][29][30][31][32][33][34][35] including Hantzsch reactions [15,[36][37][38], Michael addition [34,36,[39][40][41][42][43], Biginelli-like reaction [10,11,…”