期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 4, 期 10, 页码 974-978出版社
AMER CHEMICAL SOC
DOI: 10.1021/ml4002437
关键词
Anticancer; kinase inhibitor; EGFR; conformationally constrained
资金
- National Natural Science Foundation of China [81072516, 81273356]
- Natural Science Foundation of Zhejiang Province [Z2110655]
- Program for Zhejiang Leading Team of ST Innovation
- Osteoporosis and Breast Cancer Research Center, USA
This letter describes the construction of conformationally constrained quinazoline analogues. Structure-activity relationship studies led to the identification of the lead compound 9n. Compound 9n exhibits effective in vitro activity against A431(WT,overexpression) and H1975([L858R/T790M]) cancer cell lines but is significantly less effective against EGFR negative cancer cell lines (SW620, A.549, and 1(562). Compound 9n was also assessed for potency in enzymatic assays and in vivo antitumor studies. The results indicated that 9n is a potent kinase inhibitor against both wild-type and T790M mutant EGFR kinase. Meanwhile, an oral administration of 9n at a dose of 200 mg/kg produced a considerable antitumor effect in a A431 xenograft model, as compared to gefitinib. A preliminary pharmacokinetic study of 9n also indicates it has good pharmacokinetic properties, and therefore, it is a good starting point for further development.
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