Novel T790M mutant-selective EGFR kinase inhibitors

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Novel T790M mutant-selective EGFR kinase inhibitors

机译：新型T790M突变体选择性EGFR激酶抑制剂

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The clinical efficacy of the EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs), erlotinib and gefitinib, in the treatment of non-small-cell lung cancers (NSCLCs) is among the most important breakthroughs of modern molecular cancer biology. These compounds are. effective therapies, especially against tumors harboring the previously mentioned EGFR-activating mutations. This is most probably due to the fact that these mutations increase EGFR affinity towards the TKIs, supporting more efficient competitive binding of the inhibitor at the ATP-binding site. However, exposure of cells to these compounds results in the selection of cells expressing resistant EGFR, with an additional mutation at T790M [l] at the active site, producing a receptor with a restored wild-type-like affinity towards ATP. This has led to the hypothesis that irreversible inhibitors with increased occupancy of the ATP site could be used to overcome the resistance. Thus far, such inhibitors have shown limited success owing to their ability to also inhibit the wild-type receptor, thus resulting in dose-limiting side-effects (see references in [2]),

机译：EGF受体（EGFR）酪氨酸激酶抑制剂（TKI），厄洛替尼和吉非替尼在治疗非小细胞肺癌（NSCLC）中的临床疗效是现代分子癌症生物学最重要的突破之一。这些化合物是。有效的疗法，尤其是针对具有前述EGFR激活突变的肿瘤。这很可能是由于这些突变增加了EGFR对TKI的亲和力，从而支持了抑制剂在ATP结合位点的更有效竞争结合。然而，细胞暴露于这些化合物导致选择表达抗性EGFR的细胞，在活性位点在T790M [1]处有额外的突变，从而产生对ATP具有恢复的野生型样亲和力的受体。这导致了这样的假设，即可以利用具有增加的ATP位点的不可逆抑制剂来克服耐药性。到目前为止，由于这类抑制剂还具有抑制野生型受体的能力，因此显示出有限的成功，从而导致剂量限制性副作用（参见参考文献[2]），

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《Pharmacogenomics》 |2010年第6期|共1页
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1. 第一代酪氨酸激酶抑制剂治疗中发生进展的非小细胞肺癌血浆表皮生长因子受体(EGFR) T790M突变提示了失败部位并预测了临床预后:一项前瞻性观察研究 [J] . Shirong Zhang, Lucheng Zhu, Bing Xia, 癌症（英文版） . 2018,第009期
2. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M [J] . Wenjun Zhou, Dalia Ercan, Liang Chen, Nature . 2009,第7276期

机译：新型针对EGFR T790M的突变体选择性EGFR激酶抑制剂
3. Mutant-Selective Irreversible EGFR Inhibitor, Naquotinib, Inhibits Tumor Growth in NSCLC Models with EGFR-Activating Mutations, T790M Mutation, and AXL Overexpression [J] . Hiroaki Tanaka, Hideki Sakagami, Naoki Kaneko, Molecular cancer therapeutics . 2019,第8期

机译：突变体选择性不可逆EGFR抑制剂Naquotinib抑制NSCLC模型中的肿瘤生长，具有EGFR激活突变，T790M突变和AXL过表达
4. MA16.06 Phase I/II Study of AC0010, Mutant-Selective EGFR Inhibitor, in Non-Small Cell Lung Cancer (NSCLC) Patients with EGFR T790M Mutation [J] . Yi Long Wu, Qing Zhou, Xiaoqing Liu, Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer . 2017,第1期

机译：MA16.06期I / II研究AC0010，突变选择性EGFR抑制剂，非小细胞肺癌（NSCLC）患者EGFR T790M突变患者
5. Predictive Efficacy of Low Burden EGFR Mutation Detected by Next-Generation Sequencing on Response to EGFR Tyrosine Kinase Inhibitors in Non-Small-Cell Lung Carcinoma [C] . Yeul Hong Kim, Hye Sook Kim, Jae Sook Sung, Molecular Medicine TRI-CON. . 2014

机译：下一代测序对非小细胞肺癌抗蛋白酶激酶抑制剂进行下一代测序检测的低负荷EGFR突变的预测疗效
6. Targeting EGFR and ErbB2 by small molecule tyrosine kinase inhibitors in human colon cancer. [D] . Zhou, Yunfei. 2005

机译：小分子酪氨酸激酶抑制剂在人结肠癌中靶向EGFR和ErbB2。
7. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M [O] . Wenjun Zhou, Dalia Ercan, Liang Chen, -1

机译：新型突变体选择性EGFR激酶抑制剂对EGFR T790M
8. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M [O] . Wenjun Zhou, Dalia Ercan, Liang Chen, 2009

机译：新型突变体选择性EGFR激酶抑制剂对EGFR T790M

Novel T790M mutant-selective EGFR kinase inhibitors

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