Design, synthesis and pharmacological evaluation of N4,N6-disubstituted pyrimidine-4,6-diamine derivatives as potent EGFR inhibitors in non-small cell lung cancer

• Published in: European journal of medicinal chemistry 2018-09, Vol.157, p.1300-1325
• Main Authors: Zhang, Yuan, Lv, Handeng, Luo, Lu, Xu, Yong, Pan, Yaqian, Wang, Yuewu, Lin, Han, Xiong, Jianhua, Guo, Ping, Zhang, Jinsan, Li, Xiaokun, Ye, Faqing
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; EGFR-TKIs; Female; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Structure; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; NSCLC; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Rats; Rats, Sprague-Dawley; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - metabolism; Scaffold hopping; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.08.031

▪A novel series of 4, 6-disubstituted pyrimidines derivatives were designed, synthesized, and evaluated as epidermal growth factor receptor (EGFR) inhibitors for non-small cell lung cancer(NSCLC). 4, 6-disubstituted pyrimidines as core structure was utilized to substitute the lead structure AZD3759 of the quinazoline basic skeleton via an approach involving scaffold hopping. It was found that compound Yfq07 exhibited the best inhibitory effect compared with AZD3759 in vitro and in vivo: Yfq07 exhibited a competitive ATP inhibitory effect, multiple target effects, and further featured a stronger activity against H3255, A431, HCC827, PC-9 and H1975 compared to AZD3759. Moreover, a stronger pro-apoptotic effect, inhibition of cell G2/M phase on A431, H3255, HCC827 and H1975 could also be observed. In this study, the ultimate goal was changing the core structure to improve other epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) properties while retaining the overall potency. Yfq07 was further explored as an effective 4, 6-pyrimidine anticancer agent for the treatment of human NSCLC. [Display omitted] •A novel series of 4, 6-disubstituted pyrimidines derivatives were designed and synthesized.•Compound Yfq07 showed the best activity in a MTT assay.•Compound Yfq07 blocked EGFR/Akt and ERK1/2 pathway and was selected for cell cycle analysis, apoptosis assay.•Compound Yfq07 showed potential inhibitory activity in a PC-9 xenograft model in vivo.