title: 6-Oxooxazolidine-quinazolines as noncovalent inhibitors with the potential to target mutant forms of EGFR.
abstract: Despite the remarkable benefits of gefitinib, the clinical efficacy is eventually diminished due to the acquired point mutations in the EGFR (T790M). To address this unmet medical need, we demonstrated a strategy to prepare a hybrid analogue consisting of the oxooxazolidine ring and the quinazoline scaffold and provided alternative noncovalent inhibitors targeting mutant forms of EGFR. Most of the derivatives displayed moderate to good anti-proliferative activity against gefitinib-resistant NCI-H1975. Some of them exhibited potent EGFR kinase inhibitory activities, especially on EGFR(T790M) and EGFR(L858R) kinases. SAR studies led to the identification of a hit 9a that can target both of the most common EGFR mutants: L858R and T790M. Also, 9a displayed weaker inhibitory against cancer cell lines with low level of EGFR expression and good chemical stability under different pH conditions. The work presented herein showed the potential for developing noncovalent inhibitors targeting EGFR mutants.
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058, PR China.
authors.forename: Jiaan
authors.initials: J
authors.lastname: Shao
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058, PR China.
authors.forename: En
authors.initials: E
authors.lastname: Chen
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058, PR China.
authors.forename: Ke
authors.initials: K
authors.lastname: Shu
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058, PR China. Electronic address: wentengchen@zju.edu.cn.
authors.forename: Wenteng
authors.initials: W
authors.lastname: Chen
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058, PR China. Electronic address: guolinzhang@zju.edu.cn.
authors.forename: Guolin
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058, PR China. Electronic address: yyu@zju.edu.cn.
authors.forename: Yongping
authors.initials: Y
authors.lastname: Yu
mesh_terms: D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics*; D006801:Humans; D020128:Inhibitory Concentration 50; D009154:Mutation; D066244:Proton Magnetic Resonance Spectroscopy; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D011799:Quinazolines; D066246:ErbB Receptors
keywords: Drug resistance; Hybrids; Noncovalent EGFR inhibitors; Oxooxazolidine; Quinazoline