title: AST1306, a novel irreversible inhibitor of the epidermal growth factor receptor 1 and 2, exhibits antitumor activity both in vitro and in vivo.
abstract: Despite the initial response to the reversible, ATP-competitive quinazoline inhibitors that target ErbB-family, such a subset of cancer patients almost invariably develop resistance. Recent studies have provided compelling evidence that irreversible ErbB inhibitors have the potential to override this resistance. Here, we found that AST1306, a novel anilino-quinazoline compound, inhibited the enzymatic activities of wild-type epidermal growth factor receptor (EGFR) and ErbB2 as well as EGFR resistant mutant in both cell-free and cell-based systems. Importantly, AST1306 functions as an irreversible inhibitor, most likely through covalent interaction with Cys797 and Cys805 in the catalytic domains of EGFR and ErbB2, respectively. Further studies showed that AST1306 inactivated pathways downstream of these receptors and thereby inhibited the proliferation of a panel of cancer cell lines. Although the activities of EGFR and ErbB2 were similarly sensitive to AST1306, ErbB2-overexpressing cell lines consistently exhibited more sensitivity to AST1306 antiproliferative effects. Consistent with this, knockdown of ErbB2, but not EGFR, decreased the sensitivity of SK-OV-3 cells to AST1306. In vivo, AST1306 potently suppressed tumor growth in ErbB2-overexpressing adenocarcinoma xenograft and FVB-2/N(neu) transgenic breast cancer mouse models, but weakly inhibited the growth of EGFR-overexpressing tumor xenografts. Tumor growth inhibition induced by a single dose of AST1306 in the SK-OV-3 xenograft model was accompanied by a rapid (within 2 h) and sustained (≥24 h) inhibition of both EGFR and ErbB2, consistent with an irreversible inhibition mechanism. Taken together, these results establish AST1306 as a selective, irreversible ErbB2 and EGFR inhibitor whose growth-inhibitory effects are more potent in ErbB2-overexpressing cells.
authors.affiliation: State Key Laboratory of Drug Research, Division of Antitumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Xie
authors.forename: Liping
authors.initials: L
authors.lastname: Lin
authors.forename: Linjiang
authors.initials: L
authors.lastname: Tong
authors.forename: Yong
authors.initials: Y
authors.lastname: Jiang
authors.forename: Mingyue
authors.initials: M
authors.lastname: Zheng
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Chen
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Jiang
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zhang
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Ren
authors.forename: Wenchao
authors.initials: W
authors.lastname: Qu
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Hua
authors.initials: H
authors.lastname: Wan
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Jianping
authors.initials: J
authors.lastname: Zuo
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Meiyu
authors.initials: M
authors.lastname: Geng
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
mesh_terms: D000178:Acrylamides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000596:Amino Acids; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011799:Quinazolines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000178:Acrylamides; D000596:Amino Acids; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D050505:Mutant Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C568037:AST 1306