Recent Progress of Small-Molecule Epidermal Growth Factor Receptor (EGFR) Inhibitors against C797S Resistance in Non-Small-Cell Lung Cancer,Journal of Medicinal Chemistry

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Recent Progress of Small-Molecule Epidermal Growth Factor Receptor (EGFR) Inhibitors against C797S Resistance in Non-Small-Cell Lung Cancer
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-11-27 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01310
Lingfeng Chen _{1,

2} , Weitao Fu ₁ , Lulu Zheng ₁ , Zhiguo Liu ₁ , Guang Liang _{1,

2}

Affiliation

The epidermal growth factor receptor (EGFR) has been a particular interest for drug development for treatment of non-small-cell lung cancer (NSCLC). The current third-generation EGFR small-molecule inhibitors, especially osimertinib, are at the forefront clinically for treatment of patients with NSCLC. However, a high percentage of these treated patients developed a tertiary cystein-797 to serine-790 (C797S) mutation in the EGFR kinase domain. This C797S mutation is thought to induce resistance to all current irreversible EGFR TKIs. In this Miniperspective, we present key mechanisms of resistance in response to third-generation EGFR TKIs, and emerging reports on novel EGFR TKIs to combat the resistance. Specifically, we analyze the allosteric and ATP-competitive inhibitors in terms of drug discovery, binding mechanism, and their potency and selectivity against EGFR harboring C797S mutations. Lastly, we provide some perspectives on new challenges and future directions in this field.

中文翻译：

小分子表皮生长因子受体（EGFR）抑制剂在非小细胞肺癌中对C797S抗性的最新进展

对于治疗非小细胞肺癌（NSCLC）的药物开发，表皮生长因子受体（EGFR）已引起特别关注。当前的第三代EGFR小分子抑制剂，特别是奥西替尼，在治疗NSCLC患者的临床上处于最前沿。但是，这些接受治疗的患者中有很大一部分在EGFR激酶域中出现了一个半胱氨酸797到丝氨酸790（C797S）突变。该C797S突变被认为可诱导对目前所有不可逆的EGFR TKI产生抗性。在此迷你视野中，我们介绍了对第三代EGFR TKI作出反应的耐药性的关键机制，以及有关对抗耐药性的新型EGFR TKI的新兴报道。具体来说，我们从药物发现，结合机制，以及它们对带有C797S突变的EGFR的效力和选择性。最后，我们提供了有关该领域新挑战和未来方向的一些观点。

更新日期：2017-11-28

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