ABTRACT

The epidermal growth factor receptor (EGFR) kinase inhibitors Gefitinib, Erlotinib, Afatinib and Osimertinib have been approved for the treatments of non-small cell lung cancer patients harboring sensitive EGFR mutations, but resistance arises rapidly. To date all approved EGFR inhibitors are ATP-competitive inhibitors, highlighting the need for therapeutic agents with alternative mechanisms of action. Allosteric kinase inhibitors offer a promising new therapeutic strategy to ATP-competitive inhibitors. The mutant-selective allosteric EGFR inhibitors EAI045 exhibited higher potency for EGFR^L858R&T790M compared to WT, which was also effective in EGFR-mutant models including those harboring the C797S mutation. However, it was not effective as a single-agent inhibitor, and require the co-administration of the anti-EGFR antibody Cetuximab. Further efforts produced a more potent analog JBJ-04-125-02, which can inhibit cell proliferation as a single-agent inhibitor. In the present study, molecular dynamics simulations and free energy calculations were performed and revealed the detailed inhibitory mechanism of JBJ-04-125-02 as more potent EGFR inhibitor. Moreover, the energy difference between HOMO and LUMO calculated by DFT implied the higher interaction of JBJ-04-125-02 than EAI045 in the active site of the EGFR. The identified key features obtained from the molecular modeling enabled us to design novel EGFR allosteric inhibitors.

Communicated by Ramaswamy H. Sarma

摘要

表皮生长因子受体 (EGFR) 激酶抑制剂吉非替尼、厄洛替尼、阿法替尼和奥希替尼已被批准用于治疗具有敏感 EGFR 突变的非小细胞肺癌患者，但耐药性迅速增加。迄今为止，所有批准的 EGFR 抑制剂都是 ATP 竞争性抑制剂，这突出了对具有替代作用机制的治疗剂的需求。变构激酶抑制剂为 ATP 竞争性抑制剂提供了一种有前途的新治疗策略。突变选择性变构 EGFR 抑制剂 EAI045 对 EGFR ^{L858R&T790M表现出更高的效力}与 WT 相比，WT 在 EGFR 突变模型中也有效，包括那些携带 C797S 突变的模型。然而，它作为单药抑制剂无效，需要与抗EGFR抗体西妥昔单抗联合给药。进一步的努力产生了一种更有效的类似物 JBJ-04-125-02，它可以作为单剂抑制剂抑制细胞增殖。在本研究中，进行了分子动力学模拟和自由能计算，揭示了 JBJ-04-125-02 作为更有效的 EGFR 抑制剂的详细抑制机制。此外，通过 DFT 计算的 HOMO 和 LUMO 之间的能量差异表明 JBJ-04-125-02 在 EGFR 活性位点的相互作用高于 EAI045。从分子建模中获得的已识别关键特征使我们能够设计新的 EGFR 变构抑制剂。

由 Ramaswamy H. Sarma 传达