State Key Laboratory of Drug Research, Division of Antitumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
PLoS One. 2011;6(7):e21487. doi: 10.1371/journal.pone.0021487. Epub 2011 Jul 18.
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.
尽管针对表皮生长因子受体 (EGFR) 家族的可逆、ATP 竞争性喹唑啉抑制剂最初取得了一定疗效，但几乎所有此类癌症患者最终都会产生耐药性。最近的研究提供了确凿的证据，证明不可逆的 EGFR 抑制剂有可能克服这种耐药性。在此，我们发现新型苯胺喹唑啉化合物 AST1306 能够在无细胞和细胞基础系统中抑制野生型 EGFR 和 ErbB2 以及 EGFR 耐药突变体的酶活性。重要的是，AST1306 作为一种不可逆抑制剂，很可能通过与 EGFR 和 ErbB2 催化结构域中的 Cys797 和 Cys805 发生共价相互作用而发挥作用。进一步的研究表明，AST1306 可使这些受体下游的信号通路失活，从而抑制一组癌细胞系的增殖。尽管 EGFR 和 ErbB2 的活性对 AST1306 同样敏感，但 ErbB2 过表达细胞系对 AST1306 的抗增殖作用始终表现出更高的敏感性。与此一致的是，敲低 ErbB2（而非 EGFR）可降低 SK-OV-3 细胞对 AST1306 的敏感性。在体内，AST1306 可强效抑制 ErbB2 过表达的腺癌异种移植瘤和 FVB-2/N(neu)转基因乳腺癌小鼠模型的肿瘤生长，但对 EGFR 过表达的肿瘤异种移植瘤的生长抑制作用较弱。在 SK-OV-3 异种移植模型中，AST1306 单次给药可迅速（2 小时内）且持续（≥24 小时）抑制 EGFR 和 ErbB2，与不可逆抑制机制一致。综上，这些结果表明 AST1306 是一种选择性、不可逆的 ErbB2 和 EGFR 抑制剂，在 ErbB2 过表达的细胞中其生长抑制作用更为显著。
