Targeting EGFR<sup>L858R/T790M</sup> and EGFR<sup>L858R/T790M/C797S</sup> resistance mutations in NSCLC: Current developments in medicinal chemistry
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- Xiaoyun Lu
- School of Pharmacy Jinan University Guangzhou China
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- Lei Yu
- Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences Guangzhou China
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- Zhang Zhang
- School of Pharmacy Jinan University Guangzhou China
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- Xiaomei Ren
- School of Pharmacy Jinan University Guangzhou China
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- Jeff B. Smaill
- Maurice Wilkins Centre for Molecular Biodiscovery University of Auckland Auckland New Zealand
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- Ke Ding
- School of Pharmacy Jinan University Guangzhou China
抄録
<jats:title>Abstract</jats:title><jats:p>Both the first‐generation reversible epidermal growth factor receptor (EGFR) inhibitors gefitinib and erlotinib and the second‐generation covalent epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI) afatinib have significantly improved the survival of non‐small‐cell lung cancer (NSCLC) patients with activating EGFR mutations. However, a secondary EGFR<jats:sup>T790M</jats:sup> mutation leads to the clinically acquired resistance to the first‐ and second‐generation EGFR‐TKIs drugs. A number of the third‐generation wild‐type sparing EGFR inhibitors, for example, WZ4002, CO1686, AZD9291, HM61713, EGF816, ASP8173, and PF0674775, have been developed, among which AZD9291 has been approved by US FDA for the treatment of NSCLC patients with EGFR<jats:sup>T790M</jats:sup>. More recently, a tertiary EGFR<jats:sup>C797S</jats:sup> mutation was reported as the dominant resistance mechanism to the third‐generation irreversible inhibitors. It is highly desirable to develop the fourth‐generation EGFR inhibitors. This review summarizes the mechanisms of acquired resistance and the latest medicinal chemistry advances on the third‐ and fourth‐generation EGFR inhibitors, with special attention being paid to the allosteric and reversible inhibitors combating the tertiary EGFR<jats:sup>C797S</jats:sup> mutation.</jats:p>
収録刊行物
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- Medicinal Research Reviews
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Medicinal Research Reviews 38 (5), 1550-1581, 2018-01-26
Wiley