title: A chemical tuned strategy to develop novel irreversible EGFR-TK inhibitors with improved safety and pharmacokinetic profiles.
abstract: Gatekeeper T790 M mutation in EGFR is the most prevalent factor underlying acquired resistance. Acrylamide-bearing quinazoline derivatives are powerful irreversible inhibitors for overcoming resistance. Nevertheless, concerns about the risk of nonspecific covalent modification have motivated the development of novel cysteine-targeting inhibitors. In this paper, we demonstrate that fluoro-substituted olefins can be tuned to alter Michael addition reactivity. Incorporation of these olefins into the quinazoline templates produced potent EGFR inhibitors with improved safety and pharmacokinetic properties. A lead compound 5a was validated against EGFR(WT), EGFR(T790M) as well as A431 and H1975 cancer cell lines. Additionally, compound 5a displayed a weaker inhibition against the EGFR-independent cancer cell line SW620 when compared with afatinib. Oral administration of 5a at a dose of 30 mg/kg induced tumor regression in a murine-EGFR(L858R/T790M) driven H1975 xenograft model. Also, 5a exhibited improved oral bioavailability and safety as well as favorable tissue distribution properties and enhanced brain uptake. These findings provide the basis of a promising strategy toward the treatment of NSCLC patients with drug resistance.
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Science, Zhejiang University , 866 Yuhangtang Road Zijin Campus, Hangzhou 310058, China.
authors.forename: Guangxin
authors.initials: G
authors.lastname: Xia
authors.forename: Wenteng
authors.initials: W
authors.lastname: Chen
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Jiaan
authors.initials: J
authors.lastname: Shao
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.forename: Leduo
authors.initials: L
authors.lastname: Zhang
authors.forename: Weixing
authors.initials: W
authors.lastname: Qi
authors.forename: Xing
authors.initials: X
authors.lastname: Sun
authors.forename: Bojun
authors.initials: B
authors.lastname: Li
authors.forename: Zhixiong
authors.initials: Z
authors.lastname: Xiang
authors.forename: Chen
authors.initials: C
authors.lastname: Ma
authors.forename: Jia
authors.initials: J
authors.lastname: Xu
authors.forename: Hailin
authors.initials: H
authors.lastname: Deng
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Li
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.forename: Hong
authors.initials: H
authors.lastname: Miao
authors.forename: Jiansheng
authors.initials: J
authors.lastname: Han
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Liu
authors.forename: Jingkang
authors.initials: J
authors.lastname: Shen
authors.forename: Yongping
authors.initials: Y
authors.lastname: Yu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D008807:Mice, Inbred BALB C; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors