First Bispecific Inhibitors of the Epidermal Growth Factor Receptor Kinase and the NF-κB Activity As Novel Anticancer Agents,Journal of Medicinal Chemistry

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First Bispecific Inhibitors of the Epidermal Growth Factor Receptor Kinase and the NF-κB Activity As Novel Anticancer Agents
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-03-28 00:00:00 , DOI: 10.1021/acs.jmedchem.6b01774
Mostafa M. Hamed _{1,

2} , Sarah S. Darwish ₂ , Jennifer Herrmann ₃ , Ashraf H. Abadi ₂ , Matthias Engel ₄

Affiliation

The activation of the NF-κB transcription factor is a major adaptive response induced upon treatment with EGFR kinase inhibitors, leading to the emergence of resistance in nonsmall cell lung cancer and other tumor types. To suppress this survival mechanism, we developed new thiourea quinazoline derivatives that are dual inhibitors of both EGFR kinase and the NF-κB activity. Optimization of the hit compound, identified in a NF-κB reporter gene assay, led to compound 9b, exhibiting a cellular IC₅₀ for NF-κB inhibition of 0.3 μM while retaining a potent EGFR kinase inhibition (IC₅₀ = 60 nM). The dual inhibitors showed a higher potency than gefitinib to inhibit cell growth of EGFR-overexpressing tumor cell lines in vitro and in a xenograft model in vivo, while no signs of toxicity were observed. An investigation of the molecular mechanism of NF-κB suppression revealed that the dual inhibitors depleted the transcriptional coactivator CREB-binding protein from the NF-κB complex in the nucleus.

中文翻译：

表皮生长因子受体激酶和NF-κB活性的第一个双特异性抑制剂作为新型抗癌药。

NF-κB转录因子的激活是用EGFR激酶抑制剂治疗后诱导的主要适应性反应，导致在非小细胞肺癌和其他肿瘤类型中出现耐药性。为了抑制这种存活机制，我们开发了新的硫脲喹唑啉衍生物，它们既是EGFR激酶又是NF-κB活性的双重抑制剂。在NF-κB报告基因分析中确定的最佳命中化合物可导致化合物9b表现出对IC的NF-κB抑制力为0.3μM的细胞IC ₅₀，同时保留了有效的EGFR激酶抑制作用（IC ₅₀= 60 nM）。在体外和体内异种移植模型中，双重抑制剂均显示出比吉非替尼更高的抑制EGFR过表达肿瘤细胞系细胞生长的效力，但未观察到毒性迹象。对NF-κB抑制的分子机制的研究表明，双重抑制剂耗尽了细胞核中NF-κB复合物的转录共激活因子CREB结合蛋白。

更新日期：2017-03-28

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