Structural Insight and Development of EGFR Tyrosine Kinase Inhibitors.
Structural Insight and Development of EGFR Tyrosine Kinase Inhibitors.
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DOI：
10.3390/molecules27030819
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发表时间：
2022-01-26
期刊：
影响因子：
--
通讯作者：
Tjahjono DH
中科院分区：
文献类型：
--
作者：
Amelia T;Kartasasmita RE;Ohwada T;Tjahjono DH
肺癌的患病率很高，每年的新病例和死亡率都在不断增加。此外，大多数非小细胞肺癌（NSCLC）患者的生存率仍然很低。尽管使用常规疗法，如酪氨酸激酶抑制剂治疗表皮生长因子受体（EGFR），该受体在大多数NSCLC病例中高表达，但患者的生存仍没有明显改善。这是由于该药物在EGFR突变个体中无效和高耐药率。因此，迫切需要开发新的抑制剂。了解EGFR的结构，包括它的激酶结构域和蛋白质的其他部分，以及它的激活机制可以加速发现针对这种蛋白质的新化合物。本研究描述了EGFR的细胞外、跨膜和细胞内结构域的结构。这项研究是在确定市售抑制剂在atp结合和变构位点的结合姿态的同时进行的，从而澄清了可以填补的研究空白。还解释了临床上使用的抑制剂的结合机制，从而有助于基于结构的新药开发。
Lung cancer has a high prevalence, with a growing number of new cases and mortality every year. Furthermore, the survival rate of patients with non-small-cell lung carcinoma (NSCLC) is still quite low in the majority of cases. Despite the use of conventional therapy such as tyrosine kinase inhibitor for Epidermal Growth Factor Receptor (EGFR), which is highly expressed in most NSCLC cases, there was still no substantial improvement in patient survival. This is due to the drug’s ineffectiveness and high rate of resistance among individuals with mutant EGFR. Therefore, the development of new inhibitors is urgently needed. Understanding the EGFR structure, including its kinase domain and other parts of the protein, and its activation mechanism can accelerate the discovery of novel compounds targeting this protein. This study described the structure of the extracellular, transmembrane, and intracellular domains of EGFR. This was carried out along with identifying the binding pose of commercially available inhibitors in the ATP-binding and allosteric sites, thereby clarifying the research gaps that can be filled. The binding mechanism of inhibitors that have been used clinically was also explained, thereby aiding the structure-based development of new drugs.
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影响因子：
4.2
作者：
Caporuscio, Fabiana;Tinivella, Annachiara;Rastelli, Giulio
通讯作者：
Rastelli, Giulio
影响因子：
7.3
作者：
Cheng, Hengmiao;Nair, Sajiv K.;Kath, John C.
通讯作者：
Kath, John C.
影响因子：
3.7
作者：
Aifa, S;Aydin, J;Hermanson, O
通讯作者：
Hermanson, O
影响因子：
4.8
作者：
Bublil, Erez M.;Pines, Gur;Yarden, Yosef
通讯作者：
Yarden, Yosef
DOI：
10.1073/pnas.0504952102
发表时间：
2005-08-02
影响因子：
11.1
作者：
Carter, TA;Wodicka, LM;Lockhart, DJ
通讯作者：
Lockhart, DJ